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Category Archives: DNA
DNA – Wikipedia
Posted: October 20, 2016 at 11:32 pm
Deoxyribonucleic acid (i;[1]DNA) is a molecule that carries the genetic instructions used in the growth, development, functioning and reproduction of all known living organisms and many viruses. DNA and RNA are nucleic acids; alongside proteins, lipids and complex carbohydrates (polysaccharides), they are one of the four major types of macromolecules that are essential for all known forms of life. Most DNA molecules consist of two biopolymer strands coiled around each other to form a double helix.
The two DNA strands are termed polynucleotides since they are composed of simpler monomer units called nucleotides.[2][3] Each nucleotide is composed of one of four nitrogen-containing nucleobaseseither cytosine (C), guanine (G), adenine (A), or thymine (T)and a sugar called deoxyribose and a phosphate group. The nucleotides are joined to one another in a chain by covalent bonds between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together (according to base pairing rules (A with T, and C with G) with hydrogen bonds to make double-stranded DNA. The total amount of related DNA base pairs on Earth is estimated at 5.0 x 1037, and weighs 50 billion tonnes.[4] In comparison, the total mass of the biosphere has been estimated to be as much as 4 trillion tons of carbon (TtC).[5]
DNA stores biological information. The DNA backbone is resistant to cleavage, and both strands of the double-stranded structure store the same biological information. This information is replicated as and when the two strands separate. A large part of DNA (more than 98% for humans) is non-coding, meaning that these sections do not serve as patterns for protein sequences.
The two strands of DNA run in opposite directions to each other and are thus antiparallel. Attached to each sugar is one of four types of nucleobases (informally, bases). It is the sequence of these four nucleobases along the backbone that encodes biological information. RNA strands are created using DNA strands as a template in a process called transcription. Under the genetic code, these RNA strands are translated to specify the sequence of amino acids within proteins in a process called translation.
Within eukaryotic cells, DNA is organized into long structures called chromosomes. During cell division these chromosomes are duplicated in the process of DNA replication, providing each cell its own complete set of chromosomes. Eukaryotic organisms (animals, plants, fungi, and protists) store most of their DNA inside the cell nucleus and some of their DNA in organelles, such as mitochondria or chloroplasts.[6] In contrast, prokaryotes (bacteria and archaea) store their DNA only in the cytoplasm. Within the eukaryotic chromosomes, chromatin proteins such as histones compact and organize DNA. These compact structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed.
DNA was first isolated by Friedrich Miescher in 1869. Its molecular structure was identified by James Watson and Francis Crick in 1953, whose model-building efforts were guided by X-ray diffraction data acquired by Rosalind Franklin. DNA is used by researchers as a molecular tool to explore physical laws and theories, such as the ergodic theorem and the theory of elasticity. The unique material properties of DNA have made it an attractive molecule for material scientists and engineers interested in micro- and nano-fabrication. Among notable advances in this field are DNA origami and DNA-based hybrid materials.[7]
DNA is a long polymer made from repeating units called nucleotides.[8][9] The structure of DNA is non-static,[10] all species comprises two helical chains each coiled round the same axis, and each with a pitch of 34ngstrms (3.4nanometres) and a radius of 10ngstrms (1.0nanometre).[11] According to another study, when measured in a particular solution, the DNA chain measured 22 to 26ngstrms wide (2.2 to 2.6nanometres), and one nucleotide unit measured 3.3 (0.33nm) long.[12] Although each individual repeating unit is very small, DNA polymers can be very large molecules containing millions of nucleotides. For instance, the DNA in the largest human chromosome, chromosome number 1, consists of approximately 220 million base pairs[13] and would be 85mm long if straightened.
In living organisms DNA does not usually exist as a single molecule, but instead as a pair of molecules that are held tightly together.[14][15] These two long strands entwine like vines, in the shape of a double helix. The nucleotide contains both a segment of the backbone of the molecule (which holds the chain together) and a nucleobase (which interacts with the other DNA strand in the helix). A nucleobase linked to a sugar is called a nucleoside and a base linked to a sugar and one or more phosphate groups is called a nucleotide. A polymer comprising multiple linked nucleotides (as in DNA) is called a polynucleotide.[16]
The backbone of the DNA strand is made from alternating phosphate and sugar residues.[17] The sugar in DNA is 2-deoxyribose, which is a pentose (five-carbon) sugar. The sugars are joined together by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These asymmetric bonds mean a strand of DNA has a direction. In a double helix, the direction of the nucleotides in one strand is opposite to their direction in the other strand: the strands are antiparallel. The asymmetric ends of DNA strands are said to have a directionality of five prime (5) and three prime (3), with the 5 end having a terminal phosphate group and the 3 end a terminal hydroxyl group. One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being replaced by the alternative pentose sugar ribose in RNA.[15]
The DNA double helix is stabilized primarily by two forces: hydrogen bonds between nucleotides and base-stacking interactions among aromatic nucleobases.[19] In the aqueous environment of the cell, the conjugated bonds of nucleotide bases align perpendicular to the axis of the DNA molecule, minimizing their interaction with the solvation shell. The four bases found in DNA are adenine (A), cytosine (C), guanine (G) and thymine (T). These four bases are attached to the sugar-phosphate to form the complete nucleotide, as shown for adenosine monophosphate. Adenine pairs with thymine and guanine pairs with cytosine. It was represented by A-T base pairs and G-C base pairs.[20][21]
The nucleobases are classified into two types: the purines, A and G, being fused five- and six-membered heterocyclic compounds, and the pyrimidines, the six-membered rings C and T.[15] A fifth pyrimidine nucleobase, uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring. In addition to RNA and DNA, many artificial nucleic acid analogues have been created to study the properties of nucleic acids, or for use in biotechnology.[22]
Uracil is not usually found in DNA, occurring only as a breakdown product of cytosine. However, in several bacteriophages, Bacillus subtilis bacteriophages PBS1 and PBS2 and Yersinia bacteriophage piR1-37, thymine has been replaced by uracil.[23] Another phage - Staphylococcal phage S6 - has been identified with a genome where thymine has been replaced by uracil.[24]
Base J (beta-d-glucopyranosyloxymethyluracil), a modified form of uracil, is also found in several organisms: the flagellates Diplonema and Euglena, and all the kinetoplastid genera.[25] Biosynthesis of J occurs in two steps: in the first step a specific thymidine in DNA is converted into hydroxymethyldeoxyuridine; in the second HOMedU is glycosylated to form J.[26] Proteins that bind specifically to this base have been identified.[27][28][29] These proteins appear to be distant relatives of the Tet1 oncogene that is involved in the pathogenesis of acute myeloid leukemia.[30] J appears to act as a termination signal for RNA polymerase II.[31][32]
Twin helical strands form the DNA backbone. Another double helix may be found tracing the spaces, or grooves, between the strands. These voids are adjacent to the base pairs and may provide a binding site. As the strands are not symmetrically located with respect to each other, the grooves are unequally sized. One groove, the major groove, is 22 wide and the other, the minor groove, is 12 wide.[33] The width of the major groove means that the edges of the bases are more accessible in the major groove than in the minor groove. As a result, proteins such as transcription factors that can bind to specific sequences in double-stranded DNA usually make contact with the sides of the bases exposed in the major groove.[34] This situation varies in unusual conformations of DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in size that would be seen if the DNA is twisted back into the ordinary B form.
In a DNA double helix, each type of nucleobase on one strand bonds with just one type of nucleobase on the other strand. This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with adenine bonding only to thymine in two hydrogen bonds, and cytosine bonding only to guanine in three hydrogen bonds. This arrangement of two nucleotides binding together across the double helix is called a base pair. As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can thus be pulled apart like a zipper, either by a mechanical force or high temperature.[35] As a result of this base pair complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. This reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms.[9]
The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC forming three hydrogen bonds (see figures, right). DNA with high GC-content is more stable than DNA with low GC-content.
As noted above, most DNA molecules are actually two polymer strands, bound together in a helical fashion by noncovalent bonds; this double stranded structure (dsDNA) is maintained largely by the intrastrand base stacking interactions, which are strongest for G,C stacks. The two strands can come apart a process known as melting to form two single-stranded DNA molecules (ssDNA) molecules. Melting occurs at high temperature, low salt and high pH (low pH also melts DNA, but since DNA is unstable due to acid depurination, low pH is rarely used).
The stability of the dsDNA form depends not only on the GC-content (% G,C basepairs) but also on sequence (since stacking is sequence specific) and also length (longer molecules are more stable). The stability can be measured in various ways; a common way is the "melting temperature", which is the temperature at which 50% of the ds molecules are converted to ss molecules; melting temperature is dependent on ionic strength and the concentration of DNA. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determines the strength of the association between the two strands of DNA. Long DNA helices with a high GC-content have stronger-interacting strands, while short helices with high AT content have weaker-interacting strands.[36] In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in some promoters, tend to have a high AT content, making the strands easier to pull apart.[37]
In the laboratory, the strength of this interaction can be measured by finding the temperature necessary to break the hydrogen bonds, their melting temperature (also called Tm value). When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules (ssDNA) have no single common shape, but some conformations are more stable than others.[38]
A DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA copy that is translated into protein.[39] The sequence on the opposite strand is called the "antisense" sequence. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands can contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear.[40] One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.[41]
A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between sense and antisense strands by having overlapping genes.[42] In these cases, some DNA sequences do double duty, encoding one protein when read along one strand, and a second protein when read in the opposite direction along the other strand. In bacteria, this overlap may be involved in the regulation of gene transcription,[43] while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.[44]
DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound.[45] If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases.[46] These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.[47]
DNA exists in many possible conformations that include A-DNA, B-DNA, and Z-DNA forms, although, only B-DNA and Z-DNA have been directly observed in functional organisms.[17] The conformation that DNA adopts depends on the hydration level, DNA sequence, the amount and direction of supercoiling, chemical modifications of the bases, the type and concentration of metal ions, and the presence of polyamines in solution.[48]
The first published reports of A-DNA X-ray diffraction patternsand also B-DNAused analyses based on Patterson transforms that provided only a limited amount of structural information for oriented fibers of DNA.[49][50] An alternative analysis was then proposed by Wilkins et al., in 1953, for the in vivo B-DNA X-ray diffraction-scattering patterns of highly hydrated DNA fibers in terms of squares of Bessel functions.[51] In the same journal, James Watson and Francis Crick presented their molecular modeling analysis of the DNA X-ray diffraction patterns to suggest that the structure was a double-helix.[11]
Although the B-DNA form is most common under the conditions found in cells,[52] it is not a well-defined conformation but a family of related DNA conformations[53] that occur at the high hydration levels present in living cells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with a significant degree of disorder.[54][55]
Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and a narrower, deeper major groove. The A form occurs under non-physiological conditions in partly dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, and in enzyme-DNA complexes.[56][57] Segments of DNA where the bases have been chemically modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form.[58] These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription.[59]
For many years exobiologists have proposed the existence of a shadow biosphere, a postulated microbial biosphere of Earth that uses radically different biochemical and molecular processes than currently known life. One of the proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA. A report in 2010 of the possibility in the bacterium GFAJ-1, was announced,[60][60][61] though the research was disputed,[61][62] and evidence suggests the bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules.[63]
At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3 ends of chromosomes.[64] These specialized chromosome caps also help protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected.[65] In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.[66]
These guanine-rich sequences may stabilize chromosome ends by forming structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases form a flat plate and these flat four-base units then stack on top of each other, to form a stable G-quadruplex structure.[68] These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit.[69] Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure.
In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins.[70] At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.[68]
In DNA, fraying occurs when non-complementary regions exist at the end of an otherwise complementary double-strand of DNA. However, branched DNA can occur if a third strand of DNA is introduced and contains adjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplest example of branched DNA involves only three strands of DNA, complexes involving additional strands and multiple branches are also possible.[71] Branched DNA can be used in nanotechnology to construct geometric shapes, see the section on uses in technology below.
The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin. Base modifications can be involved in packaging, with regions that have low or no gene expression usually containing high levels of methylation of cytosine bases. DNA packaging and its influence on gene expression can also occur by covalent modifications of the histone protein core around which DNA is wrapped in the chromatin structure or else by remodeling carried out by chromatin remodeling complexes (see Chromatin remodeling). There is, further, crosstalk between DNA methylation and histone modification, so they can coordinately affect chromatin and gene expression.[72]
For one example, cytosine methylation, produces 5-methylcytosine, which is important for X-inactivation of chromosomes.[73] The average level of methylation varies between organisms the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine.[74] Despite the importance of 5-methylcytosine, it can deaminate to leave a thymine base, so methylated cytosines are particularly prone to mutations.[75] Other base modifications include adenine methylation in bacteria, the presence of 5-hydroxymethylcytosine in the brain,[76] and the glycosylation of uracil to produce the "J-base" in kinetoplastids.[77][78]
DNA can be damaged by many sorts of mutagens, which change the DNA sequence. Mutagens include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and X-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light can damage DNA by producing thymine dimers, which are cross-links between pyrimidine bases.[80] On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, and double-strand breaks.[81] A typical human cell contains about 150,000 bases that have suffered oxidative damage.[82] Of these oxidative lesions, the most dangerous are double-strand breaks, as these are difficult to repair and can produce point mutations, insertions, deletions from the DNA sequence, and chromosomal translocations.[83] These mutations can cause cancer. Because of inherent limits in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer.[84][85] DNA damages that are naturally occurring, due to normal cellular processes that produce reactive oxygen species, the hydrolytic activities of cellular water, etc., also occur frequently. Although most of these damages are repaired, in any cell some DNA damage may remain despite the action of repair processes. These remaining DNA damages accumulate with age in mammalian postmitotic tissues. This accumulation appears to be an important underlying cause of aging.[86][87][88]
Many mutagens fit into the space between two adjacent base pairs, this is called intercalation. Most intercalators are aromatic and planar molecules; examples include ethidium bromide, acridines, daunomycin, and doxorubicin. For an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and mutations.[89] As a result, DNA intercalators may be carcinogens, and in the case of thalidomide, a teratogen.[90] Others such as benzo[a]pyrene diol epoxide and aflatoxin form DNA adducts that induce errors in replication.[91] Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used in chemotherapy to inhibit rapidly growing cancer cells.[92]
DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes.[93] The information carried by DNA is held in the sequence of pieces of DNA called genes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation, which depends on the same interaction between RNA nucleotides. In alternative fashion, a cell may simply copy its genetic information in a process called DNA replication. The details of these functions are covered in other articles; here the focus is on the interactions between DNA and other molecules that mediate the function of the genome.
Genomic DNA is tightly and orderly packed in the process called DNA condensation, to fit the small available volumes of the cell. In eukaryotes, DNA is located in the cell nucleus, with small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid.[94] The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, and regulatory sequences such as promoters and enhancers, which control transcription of the open reading frame.
In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences.[95] The reasons for the presence of so much noncoding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species represent a long-standing puzzle known as the "C-value enigma".[96] However, some DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.[97]
Some noncoding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes, but are important for the function and stability of chromosomes.[65][99] An abundant form of noncoding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation.[100] These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.[101]
A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT).
In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (43combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA, TGA, and TAG codons.
Cell division is essential for an organism to grow, but, when a cell divides, it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing, and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5 to 3 direction, different mechanisms are used to copy the antiparallel strands of the double helix.[102] In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.
Naked extracellular DNA (eDNA), most of it released by cell death, is nearly ubiquitous in the environment. Its concentration in soil may be as high as 2 g/L, and its concentration in natural aquatic environments may be as high at 88 g/L.[103] Various possible functions have been proposed for eDNA: it may be involved in horizontal gene transfer;[104] it may provide nutrients;[105] and it may act as a buffer to recruit or titrate ions or antibiotics.[106] Extracellular DNA acts as a functional extracellular matrix component in the biofilms of several bacterial species. It may act as a recognition factor to regulate the attachment and dispersal of specific cell types in the biofilm;[107] it may contribute to biofilm formation;[108] and it may contribute to the biofilm's physical strength and resistance to biological stress.[109]
All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.
Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin. In eukaryotes this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved.[110][111] The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones, making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are thus largely independent of the base sequence.[112] Chemical modifications of these basic amino acid residues include methylation, phosphorylation and acetylation.[113] These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription.[114] Other non-specific DNA-binding proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted DNA.[115] These proteins are important in bending arrays of nucleosomes and arranging them into the larger structures that make up chromosomes.[116]
A distinct group of DNA-binding proteins are the DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein A is the best-understood member of this family and is used in processes where the double helix is separated, including DNA replication, recombination and DNA repair.[117] These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.
In contrast, other proteins have evolved to bind to particular DNA sequences. The most intensively studied of these are the various transcription factors, which are proteins that regulate transcription. Each transcription factor binds to one particular set of DNA sequences and activates or inhibits the transcription of genes that have these sequences close to their promoters. The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription.[119] Alternatively, transcription factors can bind enzymes that modify the histones at the promoter. This changes the accessibility of the DNA template to the polymerase.[120]
As these DNA targets can occur throughout an organism's genome, changes in the activity of one type of transcription factor can affect thousands of genes.[121] Consequently, these proteins are often the targets of the signal transduction processes that control responses to environmental changes or cellular differentiation and development. The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are most accessible.[34]
Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands. The most frequently used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences. For instance, the EcoRV enzyme shown to the left recognizes the 6-base sequence 5-GATATC-3 and makes a cut at the horizontal line. In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system.[123] In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.
Enzymes called DNA ligases can rejoin cut or broken DNA strands.[124] Ligases are particularly important in lagging strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a complete copy of the DNA template. They are also used in DNA repair and genetic recombination.[124]
Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of supercoiling in DNA. Some of these enzymes work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break.[46] Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix.[125] Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.[47]
Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates, predominantly adenosine triphosphate (ATP), to break hydrogen bonds between bases and unwind the DNA double helix into single strands.[126] These enzymes are essential for most processes where enzymes need to access the DNA bases.
Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of their products are created based on existing polynucleotide chainswhich are called templates. These enzymes function by repeatedly adding a nucleotide to the 3 hydroxyl group at the end of the growing polynucleotide chain. As a consequence, all polymerases work in a 5 to 3 direction.[127] In the active site of these enzymes, the incoming nucleoside triphosphate base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand of their template. Polymerases are classified according to the type of template that they use.
In DNA replication, DNA-dependent DNA polymerases make copies of DNA polynucleotide chains. To preserve biological information, it is essential that the sequence of bases in each copy are precisely complementary to the sequence of bases in the template strand. Many DNA polymerases have a proofreading activity. Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is detected, a 3 to 5 exonuclease activity is activated and the incorrect base removed.[128] In most organisms, DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases.[129]
RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres.[64][130] Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure.[65]
Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches a region of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependent DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome, operates as part of a large protein complex with multiple regulatory and accessory subunits.[131]
A DNA helix usually does not interact with other segments of DNA, and in human cells the different chromosomes even occupy separate areas in the nucleus called "chromosome territories".[133] This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is in chromosomal crossover which occurs during sexual reproduction, when genetic recombination occurs. Chromosomal crossover is when two DNA helices break, swap a section and then rejoin.
Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of natural selection and can be important in the rapid evolution of new proteins.[134] Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks.[135]
The most common form of chromosomal crossover is homologous recombination, where the two chromosomes involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known as recombinases, such as RAD51.[136] The first step in recombination is a double-stranded break caused by either an endonuclease or damage to the DNA.[137] A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA.[138]
DNA contains the genetic information that allows all modern living things to function, grow and reproduce. However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material.[139][140] RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes.[141] This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur, since the number of different bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes.[142] However, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible because DNA survives in the environment for less than one million years, and slowly degrades into short fragments in solution.[143] Claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250 million years old,[144] but these claims are controversial.[145][146]
Building blocks of DNA (adenine, guanine and related organic molecules) may have been formed extraterrestrially in outer space.[147][148][149] Complex DNA and RNA organic compounds of life, including uracil, cytosine, and thymine, have also been formed in the laboratory under conditions mimicking those found in outer space, using starting chemicals, such as pyrimidine, found in meteorites. Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in the universe, may have been formed in red giants or in interstellar cosmic dust and gas clouds.[150]
Methods have been developed to purify DNA from organisms, such as phenol-chloroform extraction, and to manipulate it in the laboratory, such as restriction digests and the polymerase chain reaction. Modern biology and biochemistry make intensive use of these techniques in recombinant DNA technology. Recombinant DNA is a man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into organisms in the form of plasmids or in the appropriate format, by using a viral vector.[151] The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research,[152] or be grown in agriculture.[153][154]
Forensic scientists can use DNA in blood, semen, skin, saliva or hair found at a crime scene to identify a matching DNA of an individual, such as a perpetrator. This process is formally termed DNA profiling, but may also be called "genetic fingerprinting". In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a matching DNA.[155] However, identification can be complicated if the scene is contaminated with DNA from several people.[156] DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys,[157] and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.[158]
The development of forensic science, and the ability to now obtain genetic matching on minute samples of blood, skin, saliva, or hair has led to re-examining many cases. Evidence can now be uncovered that was scientifically impossible at the time of the original examination. Combined with the removal of the double jeopardy law in some places, this can allow cases to be reopened where prior trials have failed to produce sufficient evidence to convince a jury. People charged with serious crimes may be required to provide a sample of DNA for matching purposes. The most obvious defence to DNA matches obtained forensically is to claim that cross-contamination of evidence has occurred. This has resulted in meticulous strict handling procedures with new cases of serious crime. DNA profiling is also used successfully to positively identify victims of mass casualty incidents,[159] bodies or body parts in serious accidents, and individual victims in mass war graves, via matching to family members.
DNA profiling is also used in DNA paternity testing to determine if someone is the biological parent or grandparent of a child with the probability of parentage is typically 99.99% when the alleged parent is biologically related to the child. Normal DNA sequencing methods happen after birth but there are new methods to test paternity while a mother is still pregnant.[160]
Deoxyribozymes, also called DNAzymes or catalytic DNA are first discovered in 1994.[161] They are mostly single stranded DNA sequences isolated from a large pool of random DNA sequences through a combinatorial approach called in vitro selection or systematic evolution of ligands by exponential enrichment (SELEX). DNAzymes catalyze variety of chemical reactions including RNA-DNA cleavage, RNA-DNA ligation, amino acids phosphorylation-dephosphorylation, carbon-carbon bond formation, and etc. DNAzymes can enhance catalytic rate of chemical reactions up to 100,000,000,000-fold over the uncatalyzed reaction.[162] The most extensively studied class of DNAzymes are RNA-cleaving types which have been used to detect different metal ions and designing therapeutic agents. Several metal-specific DNAzymes have been reported including the GR-5 DNAzyme (lead-specific),[161] the CA1-3 DNAzymes (copper-specific),[163] the 39E DNAzyme (uranyl-specific) and the NaA43 DNAzyme (sodium-specific).[164] The NaA43 DNAzyme, which is reported to be more than 10,000-fold selective for sodium over other metal ions, was used to make a real-time sodium sensor in living cells.
Bioinformatics involves the development of techniques to store, data mine, search and manipulate biological data, including DNA nucleic acid sequence data. These have led to widely applied advances in computer science, especially string searching algorithms, machine learning and database theory.[165] String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides.[166] The DNA sequence may be aligned with other DNA sequences to identify homologous sequences and locate the specific mutations that make them distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function.[167] Data sets representing entire genomes' worth of DNA sequences, such as those produced by the Human Genome Project, are difficult to use without the annotations that identify the locations of genes and regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict the presence of particular gene products and their possible functions in an organism even before they have been isolated experimentally.[168] Entire genomes may also be compared, which can shed light on the evolutionary history of particular organism and permit the examination of complex evolutionary events.
DNA nanotechnology uses the unique molecular recognition properties of DNA and other nucleic acids to create self-assembling branched DNA complexes with useful properties.[169] DNA is thus used as a structural material rather than as a carrier of biological information. This has led to the creation of two-dimensional periodic lattices (both tile-based and using the DNA origami method) and three-dimensional structures in the shapes of polyhedra.[170]Nanomechanical devices and algorithmic self-assembly have also been demonstrated,[171] and these DNA structures have been used to template the arrangement of other molecules such as gold nanoparticles and streptavidin proteins.[172]
Because DNA collects mutations over time, which are then inherited, it contains historical information, and, by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny.[173] This field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared, population geneticists can learn the history of particular populations. This can be used in studies ranging from ecological genetics to anthropology; For example, DNA evidence is being used to try to identify the Ten Lost Tribes of Israel.[174][175]
In a paper published in Nature in January 2013, scientists from the European Bioinformatics Institute and Agilent Technologies proposed a mechanism to use DNA's ability to code information as a means of digital data storage. The group was able to encode 739 kilobytes of data into DNA code, synthesize the actual DNA, then sequence the DNA and decode the information back to its original form, with a reported 100% accuracy. The encoded information consisted of text files and audio files. A prior experiment was published in August 2012. It was conducted by researchers at Harvard University, where the text of a 54,000-word book was encoded in DNA.[176][177]
DNA was first isolated by the Swiss physician Friedrich Miescher who, in 1869, discovered a microscopic substance in the pus of discarded surgical bandages. As it resided in the nuclei of cells, he called it "nuclein".[178][179] In 1878, Albrecht Kossel isolated the non-protein component of "nuclein", nucleic acid, and later isolated its five primary nucleobases.[180][181] In 1919, Phoebus Levene identified the base, sugar and phosphate nucleotide unit.[182] Levene suggested that DNA consisted of a string of nucleotide units linked together through the phosphate groups. Levene thought the chain was short and the bases repeated in a fixed order. In 1937, William Astbury produced the first X-ray diffraction patterns that showed that DNA had a regular structure.[183]
In 1927, Nikolai Koltsov proposed that inherited traits would be inherited via a "giant hereditary molecule" made up of "two mirror strands that would replicate in a semi-conservative fashion using each strand as a template".[184][185] In 1928, Frederick Griffith in his experiment discovered that traits of the "smooth" form of Pneumococcus could be transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough" form.[186][187] This system provided the first clear suggestion that DNA carries genetic informationthe AveryMacLeodMcCarty experimentwhen Oswald Avery, along with coworkers Colin MacLeod and Maclyn McCarty, identified DNA as the transforming principle in 1943.[188] DNA's role in heredity was confirmed in 1952, when Alfred Hershey and Martha Chase in the HersheyChase experiment showed that DNA is the genetic material of the T2 phage.[189]
In 1953, James Watson and Francis Crick suggested what is now accepted as the first correct double-helix model of DNA structure in the journal Nature.[11] Their double-helix, molecular model of DNA was then based on one X-ray diffraction image (labeled as "Photo 51")[190] taken by Rosalind Franklin and Raymond Gosling in May 1952, and the information that the DNA bases are paired.
Experimental evidence supporting the Watson and Crick model was published in a series of five articles in the same issue of Nature.[191] Of these, Franklin and Gosling's paper was the first publication of their own X-ray diffraction data and original analysis method that partly supported the Watson and Crick model;[50][192] this issue also contained an article on DNA structure by Maurice Wilkins and two of his colleagues, whose analysis and in vivo B-DNA X-ray patterns also supported the presence in vivo of the double-helical DNA configurations as proposed by Crick and Watson for their double-helix molecular model of DNA in the prior two pages of Nature.[51] In 1962, after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine.[193] Nobel Prizes are awarded only to living recipients. A debate continues about who should receive credit for the discovery.[194]
In an influential presentation in 1957, Crick laid out the central dogma of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis".[195] Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through the MeselsonStahl experiment.[196] Further work by Crick and coworkers showed that the genetic code was based on non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley and Marshall Warren Nirenberg to decipher the genetic code.[197] These findings represent the birth of molecular biology.
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DNA, genes and chromosomes University of Leicester
Posted: September 16, 2016 at 5:21 am
DNA
DNA (or deoxyribonucleic acid) is the molecule that carries the genetic information in all cellular forms of life and some viruses. It belongs to a class of molecules called the nucleic acids, which are polynucleotides - that is, long chains of nucleotides.
Each nucleotide consists of three components:
The backbone of the polynucleotide is a chain of sugar and phosphate molecules. Each of the sugar groups in this sugar-phosphate backbone is linked to one of the four nitrogenous bases.
Strand of polynucleotides
DNA's ability to store - and transmit - information lies in the fact that it consists of two polynucleotide strands that twist around each other to form a double-stranded helix. The bases link across the two strands in a specific manner using hydrogen bonds: cytosine (C) pairs with guanine (G), and adenine (A) pairs with thymine (T).
Double strand of polynucleotides
The double helix of the complete DNA molecule resembles a spiral staircase, with two sugar phosphate backbones and the paired bases in the centre of the helix. This structure explains two of the most important properties of the molecule. First, it can be copied or 'replicated', as each strand can act as a template for the generation of the complementary strand. Second, it can store information in the linear sequence of the nucleotides along each strand.
DNA helix showing nitrogenous bases
It is the order of the bases along a single strand that constitutes the genetic code. The four-letter 'alphabet' of A, T, G and C forms 'words' of three letters called codons. Individual codons code for specific amino acids. A gene is a sequence of nucleotides along a DNA strand - with 'start' and 'stop' codons and other regulatory elements - that specifies a sequence of amino acids that are linked together to form a protein.
So, for example, the codon AGC codes for the amino acid serine, and the codon ACC codes for the amino acid threonine.
There are a two points to note about the genetic code:
The enzyme helicase breaks the hydrogen bonds holding the two strands together, and both strands can then act as templates for the production of the opposite strand. The process is catalysed by the enzyme DNA polymerase, and includes a proofreading mechanism.
The gene is the basic physical and functional unit of heredity. It consists of a specific sequence of nucleotides at a given position on a given chromosome that codes for a specific protein (or, in some cases, an RNA molecule).
Genes consist of three types of nucleotide sequence:
The structural components of a gene
Read more about gene expression and regulation
A human being has 20,000 to 25,000 genes located on 46 chromosomes (23 pairs). These genes are known, collectively, as the human genome.
The label eukaryote is taken from the Greek for 'true nucleus', and eukaryotes (all organisms except viruses, Eubacteria and Archaea) are defined by the possession of a nucleus and other membrane-bound cell organelles.
The nucleus of each cell in our bodies contains approximately 1.8 metres of DNA in total, although each strand is less than one millionth of a centimetre thick. This DNA is tightly packed into structures called chromosomes, which consist of long chains of DNA and associated proteins. In eukaryotes, DNA molecules are tightly wound around proteins - called histone proteins - which provide structural support and play a role in controlling the activities of the genes. A strand 150 to 200 nucleotides long is wrapped twice around a core of eight histone proteins to form a structure called a nucleosome. The histone octamer at the centre of the nucleosome is formed from two units each of histones H2A, H2B, H3, and H4. The chains of histones are coiled in turn to form a solenoid, which is stabilised by the histone H1. Further coiling of the solenoids forms the structure of the chromosome proper.
Each chromosome has a p arm and a q arm. The p arm (from the French word 'petit', meaning small) is the short arm, and the q arm (the next letter in the alphabet) is the long arm. In their replicated form, each chromosome consists of two chromatids.
Chromosome unraveling to show the base pairings of the DNA
The chromosomes - and the DNA they contain - are copied as part of the cell cycle, and passed to daughter cells through the processes of mitosis and meiosis.
Read more about the cell cycle, mitosis and meiosis
Human beings have 46 chromosomes, consisting of 22 pairs of autosomes and a pair of sex chromosomes: two X sex chromosomes for females (XX) and an X and Y sex chromosome for males (XY). One member of each pair of chromosomes comes from the mother (through the egg cell); one member of each pair comes from the father (through the sperm cell).
A photograph of the chromosomes in a cell is known as a karyotype. The autosomes are numbered 1-22 in decreasing size order.
Karyotype of a human male
The prokaryotes (Greek for 'before nucleus' - including Eubacteria and Archaea) lack a discrete nucleus, and the chromosomes of prokaryotic cells are not enclosed by a separate membrane.
Most bacteria contain a single, circular chromosome. (There are exceptions: some bacteria - for example, the genus Streptomyces - possess linear chromosomes, and Vibrio cholerae, the causative agent of cholera, has two circular chromosomes.) The chromosome - together with ribosomes and proteins associated with gene expression - is located in a region of the cell cytoplasm known as the nucleoid.
The genomes of prokaryotes are compact compared with those of eukaryotes, as they lack introns, and the genes tend to be expressed in groups known as operons. The circular chromosome of the bacterium Escherichia coli consists of a DNA molecule approximately 4.6 million nucleotides long.
In addition to the main chromosome, bacteria are also characterised by the presence of extra-chromosomal genetic elements called plasmids. These relatively small circular DNA molecules usually contain genes that are not essential to growth or reproduction.
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What is DNA? | DNA Encyclopedia
Posted: September 14, 2016 at 1:08 am
In order to truly answer the question of What is DNA? one has to go back to the elementary or high school biology classes.
DNA is the complex chemical that carries genetic information.
DNA dictates life in two manners:
There are elements called chromosomes in each cell of the human body. To be more precise, each cell contains 23 pairs of chromosomes.
Youll be astonished to know that some 50 to 100 thousand genes are held within these chromosomes. Since each of these genes could take value from one of the two values of its parent cells, hence you can imagine the possible variability in this structure.
These genes are made up of what is called DNA that is Deoxyribose Nucleic Acids. Apart from these genes that carry essential genetic information and only account for 2% of DNAs structure, the rest of the 98% of DNA is still a mystery.
Biologists call it junk DNA as there are no known proteins or traits that are coded or built by this part of DNA. This junk DNA, as well as the genetic information-carrying part only, varies in structure owing to the presence of four nucleotide bases throughout the DNA in differing order and sequence.
Think of these four nucleotide bases in DNA as letters that form an alphabet. Just like the way the order of letters determines the meaning of the word that is formed, the sequence of these nucleotide bases concludes what information is available for the production of proteins that consequently take an active part in the formation and growth of the body.
Most of the DNA is present within the nucleus of the cells. This is known as nuclear DNA. Mitochondria also hold a modest quantity of DNA, which is termed as mitochondrial DNA. The latter is useful in tests related to someones distant maternal lineage.
What is great about DNA is that it has a very autonomous self-replication mechanism in action. The replication process makes use of the two strands of DNA. Each of these strands acts as a template and after going through a series of steps is converted into dual stranded DNA once again. This replication is very important because when the cell divides, the newly formed cell requires the same set of instructions for it to function and grow and the replicated DNA serves this purpose.
Summing up the answer for what is DNA, it could easily be said that its a well-designed program spanning thousands of lines of codes that has instructions for everything that the cell needs to perform.
DNA, no matter how short the acronym sounds, is a vast topic that requires serious dedication of time and energy before one can grasp what it is and how it affects the life within and around us.
This article sets the foundations for a series of articles in which we will cover various aspects of DNA, the concepts, the technology and its applications. Right now, without going into the peculiar details, we are only going to briefly introduce these topics. You can think of it as a short glossary for DNA terminology.
Learning about DNA starts with a sound knowledge of what is it made up of and how these chemicals interact with each other to form a structure that builds a DNA molecule. You have to look carefully at what essential functions DNA performs in the cell that it is located in, by the way, its present in each cell of human as well as a body of living organisms.
In most basic terms, DNA is the master plan of life that works all the way from inception to growth. It holds all of the hereditary information and passes it from generation to generation.
Once you have encountered the double helix structure of DNA, as proposed by James Watson and Francis Crick in 1953, you should move on to advance topics like DNA replication. DNA replication tells us that each DNA is able to produce an exact copy of itself and this is made possible with the help of DNA polymerase, an enzyme that takes an active role in the process. Youll also come across DNA synthesis, which is an artificial technique to produce copies of DNA and is based on the concept of DNA replication.
While DNA holds all of the information required for the cell to perform its actions and produce the essential proteins, it is important to note that DNA doesnt interfere directly with the elements of cytoplasm outside the cell nucleus and disseminates this useful information through a messenger RNA. This is done through a process called DNA transcription.
The buzz words that have really boosted the popularity of DNA among the masses are DNA cloning and DNA testing. Who has not heard of Dolly, the first ever cloned animal? DNA testing, owing to a large number of social, commercial and forensic uses, has drawn the attention towards further studies and research in DNA.
DNA is the short term for Deoxyribonucleic Acid. Almost every cell in an individuals body has the same DNA, as the DNA is located in the cell nucleons. People, most of the times, learn what is DNA and its importance for the human body, in school.
Anyway, properly understanding what DNA is, is always important, mostly if you are working in areas in which DNA results have importance on the evolution of some cases. For starter, to understand what is DNA, you need to know that it contains all the information used in the development and functioning of all living organisms.
What is the structure of DNA, is also a common question that people seem to ask?
Human DNA consists of about 3 billion bases and more than 99 percent of them are the same, for all individuals. Another important aspect of what is DNA is that it can replicate and make copies of itself. The use of DNA linked information has become more important in science and medicine, as researchers have found that it can be used to cure diseases, or better said to avoid babies from inheriting diseases their parents are suffering from. This currently, is considered to be a major goal for scientists, who are searching for treatments, cure and also for prevention when it comes to genetic conditions. DNA becomes even more important for people who think that such risks are higher in their particular cases.
Researchers aim to detect individuals who are predisposed to develop such diseases and that means that scientists can find treatments, to be used for the purpose to prevent genetic conditions. DNA is simple to understand, but the way DNA functions is more complex.
The discovery of DNA, in fact, revolutionized both science and medicine, having numerous effects on other linked domains, such as legal and social areas. Samples of DNA are, all the times, taken from the scene of a crime, and it is a safe way to find and convict criminals, being an accepted and trusted evidence in court.
What is DNA can be easily answered when you understand that it transfers hereditary information from one generation to another, determining, at the same time, the structure of cells.
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What is DNA? | DNA Encyclopedia
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Family Tree DNA – Customer Sign In
Posted: at 1:08 am
We encourage you to search for a family surname in our SURNAMES DATABASE. Our database contains family names of clients who have already ordered a DNA profile from Family Tree DNA.
After you have searched for the surname that interests you, the name will appear in the result screen with a number after the name, e.g. Bowling (62). This indicates that the name Bowling is in our database and that 62 people with that surname (or a derivative) have already ordered a DNA sample tested. It is possible that not all 62 Bowlings have been added yet to our Recent Ancestral Origins (RAO) Database as we may be awaiting the analysis from the Lab for some of them.
A link will be provided for you to order a genetic test below the result screen. If the surname you desire is not located in our database, you will receive a message entitled "Name not found," and a form will be provided below the message to enable you to order a test kit for that surname.
Posting and updating to our database is instant. After you have registered your surname, you can search again to find the name in the updated database. Happy relative hunting!
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The Structure and Function of DNA – Molecular Biology of the …
Posted: at 1:08 am
Biologists in the 1940s had difficulty in accepting DNA as the genetic material because of the apparent simplicity of its chemistry. DNA was known to be a long polymer composed of only four types of subunits, which resemble one another chemically. Early in the 1950s, DNA was first examined by x-ray diffraction analysis, a technique for determining the three-dimensional atomic structure of a molecule (discussed in Chapter 8). The early x-ray diffraction results indicated that DNA was composed of two strands of the polymer wound into a helix. The observation that DNA was double-stranded was of crucial significance and provided one of the major clues that led to the Watson-Crick structure of DNA. Only when this model was proposed did DNA's potential for replication and information encoding become apparent. In this section we examine the structure of the DNA molecule and explain in general terms how it is able to store hereditary information.
A DNA molecule consists of two long polynucleotide chains composed of four types of nucleotide subunits. Each of these chains is known as a DNA chain, or a DNA strand. Hydrogen bonds between the base portions of the nucleotides hold the two chains together (). As we saw in Chapter 2 (Panel 2-6, pp. 120-121), nucleotides are composed of a five-carbon sugar to which are attached one or more phosphate groups and a nitrogen-containing base. In the case of the nucleotides in DNA, the sugar is deoxyribose attached to a single phosphate group (hence the name deoxyribonucleic acid), and the base may be either adenine (A), cytosine (C), guanine (G), or thymine (T). The nucleotides are covalently linked together in a chain through the sugars and phosphates, which thus form a backbone of alternating sugar-phosphate-sugar-phosphate (see ). Because only the base differs in each of the four types of subunits, each polynucleotide chain in DNA is analogous to a necklace (the backbone) strung with four types of beads (the four bases A, C, G, and T). These same symbols (A, C, G, and T) are also commonly used to denote the four different nucleotidesthat is, the bases with their attached sugar and phosphate groups.
DNA and its building blocks. DNA is made of four types of nucleotides, which are linked covalently into a polynucleotide chain (a DNA strand) with a sugar-phosphate backbone from which the bases (A, C, G, and T) extend. A DNA molecule is composed of two (more...)
The way in which the nucleotide subunits are lined together gives a DNA strand a chemical polarity. If we think of each sugar as a block with a protruding knob (the 5 phosphate) on one side and a hole (the 3 hydroxyl) on the other (see ), each completed chain, formed by interlocking knobs with holes, will have all of its subunits lined up in the same orientation. Moreover, the two ends of the chain will be easily distinguishable, as one has a hole (the 3 hydroxyl) and the other a knob (the 5 phosphate) at its terminus. This polarity in a DNA chain is indicated by referring to one end as the 3 end and the other as the 5 end.
The three-dimensional structure of DNAthe double helixarises from the chemical and structural features of its two polynucleotide chains. Because these two chains are held together by hydrogen bonding between the bases on the different strands, all the bases are on the inside of the double helix, and the sugar-phosphate backbones are on the outside (see ). In each case, a bulkier two-ring base (a purine; see Panel 2-6, pp. 120121) is paired with a single-ring base (a pyrimidine); A always pairs with T, and G with C (). This complementary base-pairing enables the base pairs to be packed in the energetically most favorable arrangement in the interior of the double helix. In this arrangement, each base pair is of similar width, thus holding the sugar-phosphate backbones an equal distance apart along the DNA molecule. To maximize the efficiency of base-pair packing, the two sugar-phosphate backbones wind around each other to form a double helix, with one complete turn every ten base pairs ().
Complementary base pairs in the DNA double helix. The shapes and chemical structure of the bases allow hydrogen bonds to form efficiently only between A and T and between G and C, where atoms that are able to form hydrogen bonds (see Panel 2-3, pp. 114115) (more...)
The DNA double helix. (A) A space-filling model of 1.5 turns of the DNA double helix. Each turn of DNA is made up of 10.4 nucleotide pairs and the center-to-center distance between adjacent nucleotide pairs is 3.4 nm. The coiling of the two strands around (more...)
The members of each base pair can fit together within the double helix only if the two strands of the helix are antiparallelthat is, only if the polarity of one strand is oriented opposite to that of the other strand (see and ). A consequence of these base-pairing requirements is that each strand of a DNA molecule contains a sequence of nucleotides that is exactly complementary to the nucleotide sequence of its partner strand.
Genes carry biological information that must be copied accurately for transmission to the next generation each time a cell divides to form two daughter cells. Two central biological questions arise from these requirements: how can the information for specifying an organism be carried in chemical form, and how is it accurately copied? The discovery of the structure of the DNA double helix was a landmark in twentieth-century biology because it immediately suggested answers to both questions, thereby resolving at the molecular level the problem of heredity. We discuss briefly the answers to these questions in this section, and we shall examine them in more detail in subsequent chapters.
DNA encodes information through the order, or sequence, of the nucleotides along each strand. Each baseA, C, T, or Gcan be considered as a letter in a four-letter alphabet that spells out biological messages in the chemical structure of the DNA. As we saw in Chapter 1, organisms differ from one another because their respective DNA molecules have different nucleotide sequences and, consequently, carry different biological messages. But how is the nucleotide alphabet used to make messages, and what do they spell out?
As discussed above, it was known well before the structure of DNA was determined that genes contain the instructions for producing proteins. The DNA messages must therefore somehow encode proteins (). This relationship immediately makes the problem easier to understand, because of the chemical character of proteins. As discussed in Chapter 3, the properties of a protein, which are responsible for its biological function, are determined by its three-dimensional structure, and its structure is determined in turn by the linear sequence of the amino acids of which it is composed. The linear sequence of nucleotides in a gene must therefore somehow spell out the linear sequence of amino acids in a protein. The exact correspondence between the four-letter nucleotide alphabet of DNA and the twenty-letter amino acid alphabet of proteinsthe genetic codeis not obvious from the DNA structure, and it took over a decade after the discovery of the double helix before it was worked out. In Chapter 6 we describe this code in detail in the course of elaborating the process, known as gene expression, through which a cell translates the nucleotide sequence of a gene into the amino acid sequence of a protein.
The relationship between genetic information carried in DNA and proteins.
The complete set of information in an organism's DNA is called its genome, and it carries the information for all the proteins the organism will ever synthesize. (The term genome is also used to describe the DNA that carries this information.) The amount of information contained in genomes is staggering: for example, a typical human cell contains 2 meters of DNA. Written out in the four-letter nucleotide alphabet, the nucleotide sequence of a very small human gene occupies a quarter of a page of text (), while the complete sequence of nucleotides in the human genome would fill more than a thousand books the size of this one. In addition to other critical information, it carries the instructions for about 30,000 distinct proteins.
The nucleotide sequence of the human -globin gene. This gene carries the information for the amino acid sequence of one of the two types of subunits of the hemoglobin molecule, which carries oxygen in the blood. A different gene, the -globin (more...)
At each cell division, the cell must copy its genome to pass it to both daughter cells. The discovery of the structure of DNA also revealed the principle that makes this copying possible: because each strand of DNA contains a sequence of nucleotides that is exactly complementary to the nucleotide sequence of its partner strand, each strand can act as a template, or mold, for the synthesis of a new complementary strand. In other words, if we designate the two DNA strands as S and S, strand S can serve as a template for making a new strand S, while strand S can serve as a template for making a new strand S (). Thus, the genetic information in DNA can be accurately copied by the beautifully simple process in which strand S separates from strand S, and each separated strand then serves as a template for the production of a new complementary partner strand that is identical to its former partner.
DNA as a template for its own duplication. As the nucleotide A successfully pairs only with T, and G with C, each strand of DNA can specify the sequence of nucleotides in its complementary strand. In this way, double-helical DNA can be copied precisely. (more...)
The ability of each strand of a DNA molecule to act as a template for producing a complementary strand enables a cell to copy, or replicate, its genes before passing them on to its descendants. In the next chapter we describe the elegant machinery the cell uses to perform this enormous task.
Nearly all the DNA in a eucaryotic cell is sequestered in a nucleus, which occupies about 10% of the total cell volume. This compartment is delimited by a nuclear envelope formed by two concentric lipid bilayer membranes that are punctured at intervals by large nuclear pores, which transport molecules between the nucleus and the cytosol. The nuclear envelope is directly connected to the extensive membranes of the endoplasmic reticulum. It is mechanically supported by two networks of intermediate filaments: one, called the nuclear lamina, forms a thin sheetlike meshwork inside the nucleus, just beneath the inner nuclear membrane; the other surrounds the outer nuclear membrane and is less regularly organized ().
A cross-sectional view of a typical cell nucleus. The nuclear envelope consists of two membranes, the outer one being continuous with the endoplasmic reticulum membrane (see also Figure 12-9). The space inside the endoplasmic reticulum (the ER lumen) (more...)
The nuclear envelope allows the many proteins that act on DNA to be concentrated where they are needed in the cell, and, as we see in subsequent chapters, it also keeps nuclear and cytosolic enzymes separate, a feature that is crucial for the proper functioning of eucaryotic cells. Compartmentalization, of which the nucleus is an example, is an important principle of biology; it serves to establish an environment in which biochemical reactions are facilitated by the high concentration of both substrates and the enzymes that act on them.
Genetic information is carried in the linear sequence of nucleotides in DNA. Each molecule of DNA is a double helix formed from two complementary strands of nucleotides held together by hydrogen bonds between G-C and A-T base pairs. Duplication of the genetic information occurs by the use of one DNA strand as a template for formation of a complementary strand. The genetic information stored in an organism's DNA contains the instructions for all the proteins the organism will ever synthesize. In eucaryotes, DNA is contained in the cell nucleus.
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DNA – structure – chemguide
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DNA - STRUCTURE
This page, looking at the structure of DNA, is the first in a sequence of pages leading on to how DNA replicates (makes copies of) itself, and then to how information stored in DNA is used to make protein molecules. This material is aimed at 16 - 18 year old chemistry students. If you are interested in this from a biological or biochemical point of view, you may find these pages a useful introduction before you get more information somewhere else.
Chemistry students at UK A level (or its various equivalents) should not waste time on this. The booklet is written for A level biology students, and goes into far more detail than you will need for chemistry purposes.
A quick look at the whole structure of DNA
These days, most people know about DNA as a complex molecule which carries the genetic code. Most will also have heard of the famous double helix.
I'm going to start with a diagram of the whole structure, and then take it apart to see how it all fits together. The diagram shows a tiny bit of a DNA double helix.
Normally I prefer to draw my own diagrams, but my drawing software isn't sophisticated enough to produce convincing twisted "ribbons".
Exploring a DNA chain
The sugars in the backbone
The backbone of DNA is based on a repeated pattern of a sugar group and a phosphate group. The full name of DNA, deoxyribonucleic acid, gives you the name of the sugar present - deoxyribose.
Deoxyribose is a modified form of another sugar called ribose. I'm going to give you the structure of that first, because you will need it later anyway. Ribose is the sugar in the backbone of RNA, ribonucleic acid.
This diagram misses out the carbon atoms in the ring for clarity. Each of the four corners where there isn't an atom shown has a carbon atom.
The heavier lines are coming out of the screen or paper towards you. In other words, you are looking at the molecule from a bit above the plane of the ring.
So that's ribose. Deoxyribose, as the name might suggest, is ribose which has lost an oxygen atom - "de-oxy".
The only other thing you need to know about deoxyribose (or ribose, for that matter) is how the carbon atoms in the ring are numbered.
The carbon atom to the right of the oxygen as we have drawn the ring is given the number 1, and then you work around to the carbon on the CH2OH side group which is number 5.
You will notice that each of the numbers has a small dash by it - 3' or 5', for example. If you just had ribose or deoxyribose on its own, that wouldn't be necessary, but in DNA and RNA these sugars are attached to other ring compounds. The carbons in the sugars are given the little dashes so that they can be distinguished from any numbers given to atoms in the other rings.
You read 3' or 5' as "3-prime" or "5-prime".
Attaching a phosphate group
The other repeating part of the DNA backbone is a phosphate group. A phosphate group is attached to the sugar molecule in place of the -OH group on the 5' carbon.
I don't want to get bogged down in this. The version I am using is fine for chemistry purposes, and will make it easy to see how the DNA backbone is put together. We are soon going to simplify all this down anyway!
Attaching a base and making a nucleotide
The final piece that we need to add to this structure before we can build a DNA strand is one of four complicated organic bases. In DNA, these bases are cytosine (C), thymine (T), adenine (A) and guanine (G).
These bases attach in place of the -OH group on the 1' carbon atom in the sugar ring.
What we have produced is known as a nucleotide.
We now need a quick look at the four bases. If you need these in a chemistry exam at this level, the structures will almost certainly be given to you.
Here are their structures:
The nitrogen and hydrogen atoms shown in blue on each molecule show where these molecules join on to the deoxyribose. In each case, the hydrogen is lost together with the -OH group on the 1' carbon atom of the sugar. This is a condensation reaction - two molecules joining together with the loss of a small one (not necessarily water).
For example, here is what the nucleotide containing cytosine would look like:
Joining the nucleotides into a DNA strand
A DNA strand is simply a string of nucleotides joined together. I can show how this happens perfectly well by going back to a simpler diagram and not worrying about the structure of the bases.
The phosphate group on one nucleotide links to the 3' carbon atom on the sugar of another one. In the process, a molecule of water is lost - another condensation reaction.
. . . and you can continue to add more nucleotides in the same way to build up the DNA chain.
Now we can simplify all this down to the bare essentials!
Both are right and, equally, both are misleading! The shape of the bonds around the phosphorus atom is tetrahedral, and all of the bonds are at approximately 109 to each other. Whichever way you choose to draw this in 2-dimensions on paper, it still represents the same molecule in reality.
To take a simpler example, if you draw a structural formula for CH2Cl2 using simple bond notation, you could equally well draw the chlorine atoms at right angles to each other or opposite each other. The molecule would still be exactly the same. This is one of the things you had to learn when you first started drawing structures for organic molecules. If you still aren't sure about this, look again at the page about drawing organic molecules.
Building a DNA chain concentrating on the essentials
What matters in DNA is the sequence the four bases take up in the chain. We aren't particularly interested in the backbone, so we can simplify that down. For the moment, we can simplify the precise structures of the bases as well.
We can build the chain based on this fairly obvious simplification:
There is only one possible point of confusion here - and that relates to how the phosphate group, P, is attached to the sugar ring. Notice that it is joined via two lines with an angle between them.
By convention, if you draw lines like this, there is a carbon atom where these two lines join. That is the carbon atom in the CH2 group if you refer back to a previous diagram. If you had tried to attach the phosphate to the ring by a single straight line, that CH2 group would have got lost!
Joining up lots of these gives you a part of a DNA chain. The diagram below is a bit from the middle of a chain. Notice that the individual bases have been identified by the first letters of the base names. (A = adenine, etc). Notice also that there are two different sizes of base. Adenine and guanine are bigger because they both have two rings. Cytosine and thymine only have one ring each.
If the top of this segment was the end of the chain, then the phosphate group would have an -OH group attached to the spare bond rather than another sugar ring.
Similarly, if the bottom of this segment of chain was the end, then the spare bond at the bottom would also be to an -OH group on the deoxyribose ring.
Joining the two DNA chains together
The importance of "base pairs"
Have another look at the diagram we started from:
If you look at this carefully, you will see that an adenine on one chain is always paired with a thymine on the second chain. And a guanine on one chain is always paired with a cytosine on the other one.
So how exactly does this work?
The first thing to notice is that a smaller base is always paired with a bigger one. The effect of this is to keep the two chains at a fixed distance from each other all the way along.
But, more than this, the pairing has to be exactly . . .
That is because these particular pairs fit exactly to form very effective hydrogen bonds with each other. It is these hydrogen bonds which hold the two chains together.
The base pairs fit together as follows.
The A-T base pair:
The G-C base pair:
If you try any other combination of base pairs, they won't fit!
If hydrogen bonding worries you, follow this link for detailed explanations. Use the BACK button on your browser to return here later.
A final structure for DNA showing the important bits
Notice that the two chains run in opposite directions, and the right-hand chain is essentially upside-down. You will also notice that I have labelled the ends of these bits of chain with 3' and 5'.
If you followed the left-hand chain to its very end at the top, you would have a phosphate group attached to the 5' carbon in the deoxyribose ring. If you followed it all the way to the other end, you would have an -OH group attached to the 3' carbon.
In the second chain, the top end has a 3' carbon, and the bottom end a 5'.
This 5' and 3' notation becomes important when we start talking about the genetic code and genes. The genetic code in genes is always written in the 5' to 3' direction along a chain.
It is also important when we take a very simplified look at how DNA makes copies of itself on the next page . . .
To the next page about DNA . . .
To the amino acid and other biochemistry menu . . .
To the menu of other organic compounds . . .
To Main Menu . . .
Jim Clark 2007 (modified May 2016)
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DNA – Definition by AcronymFinder
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DNA Department(al) Network Administrator DNA Does Not Apply DNA Deoxyribonucleic Acid DNA Genentech, Inc (stock symbol) DNA Data Not Available DNA Dermatology Nurses' Association DNA Directia Nationala Anticoruptie (Romanian) DNA Defense Nuclear Agency DNA Do Not Adopt (used by animal shelters to refer to animal abusers) DNA Det Norske Arbeiderparti (Norwegian Labour Party) DNA Distributed Internet Applications Architecture (Microsoft) DNA Dynamic Network Administration (Ericsson) DNA De Nieuw Amsterdam (theater group) DNA Distributed Network Attack DNA Do Not Announce (hospital patient privacy) DnA Do Not Abbreviate (online gaming clan) DNA Deutscher Normenausschuss (German Committee of Standards) DNA National Dyslexia Association (humor) DNA Direct Network Access DNA Dernire Nouvelles d'Alsace (French newspaper) DNA DoNotAge (OSPF) DNA Datanetwork Associates (Software) DNA Dinebeiina Nahiilna be Agaditahe (Navajo legal counselors) DNA Did Not Answer DNA Did Not Attend DNA Do Not Ask DNA Definitely Not Attractive DNA Down Auxiliary DNA Distributed Internetwork Architecture (Microsoft) DNA Did Not Attack (Dana Carvey) DNA Do Not Approve DNA Do Not Answer (cell phone) DNA Do Not Admit DNA Drug 'n Alcohol (band) DNA Diversified Naval Architects, Inc. (Ottawa, Ontario, Canada) DNA Dorchester Neighborhood Association (Waldorf, Maryland) DNA Djibouti National Army DNA Digital Narrowband Analysis DNA Distributed Networking Agent DNA Downriver Numismatic Association DNA Designated National Authority DNA Douglas Noel Adams (late British author of the Hitchhiker's Guide to the Galaxy series) DNA Development Needs Analysis DNA Digital Network Architecture DNA Digital Nonlinear Accelerator DNA Direction de la Navigation Arienne (French: Directorate of Air Navigation; Morocco) DNA Direction Nationale de l'Arbitrage (French: National Directorate of Arbitration) DNA Direzione Nazionale Antimafia (Italian: National Anti-Mafia Directorate) DNA Distributed interNet Applications DNA Detroit News Agency DNA Die Neue Allianz (German: The New Alliance) DNA Dernires Nouvelles d'Algrie (French: Latest News from Algeria) DNA Department of Native Affairs (various locations) DNA Dpense Non Admise (French: Non-Deductible Expense) DNA Delaware Nurses Association DNA Delayed Neutron Activation DNA Delivery Network Accelerator (BitTorrent) DNA Delta Nu Alpha DNA Denver Newspaper Agency (Denver, CO) DNA Daily News and Analysis (India; newspaper) DNA Dark Native Apostle (gaming) DNA Domain Name Authority (various locations) DNA Doctors Net Access DNA Distribution Nationale Airsoft (French airsoft supply company) DNA Distributed Network Analyzer DNA Do Not Abbreviate DNA Dynamic Network Analyzer (Lucent) DNA Dynamic Network Architecture
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Chapter 1: How Genes Work: The New Genetics – National …
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People have known for many years that living things inherit traits from their parents. That common-sense observation led to agriculture, the purposeful breeding and cultivation of animals and plants for desirable characteristics. Firming up the details took quite some time, though. Researchers did not understand exactly how traits were passed to the next generation until the middle of the 20th century.
Now it is clear that genes are what carry our traits through generations and that genes are made of deoxyribonucleic acid (DNA). But genes themselves don't do the actual work. Rather, they serve as instruction books for making functional molecules such as ribonucleic acid (RNA) and proteins, which perform the chemical reactions in our bodies.
Proteins do many other things, too. They provide the body's main building materials, forming the cell's architecture and structural components. But one thing proteins can't do is make copies of themselves. When a cell needs more proteins, it uses the manufacturing instructions coded in DNA.
The DNA code of a genethe sequence of its individual DNA building blocks, labeled A (adenine), T (thymine), C (cytosine) and G (guanine) and collectively called nucleotides spells out the exact order of a protein's building blocks, amino acids.
Occasionally, there is a kind of typographical error in a gene's DNA sequence. This mistake which can be a change, gap or duplicationis called a mutation.
A mutation can cause a gene to encode a protein that works incorrectly or that doesn't work at all. Sometimes, the error means that no protein is made.
But not all DNA changes are harmful. Some mutations have no effect, and others produce new versions of proteins that may give a survival advantage to the organisms that have them. Over time, mutations supply the raw material from which new life forms evolve (see Chapter 3, "Life's Genetic Tree").
The monk Gregor Mendel first described how traits are inherited from one generation to the next.
In 1900, three European scientists independently discovered an obscure research paper that had been published nearly 35 years before. Written by Gregor Mendel, an Austrian monk who was also a scientist, the report described a series of breeding experiments performed with pea plants growing in his abbey garden.
Mendel had studied how pea plants inherited the two variant forms of easy-to-see traits. These included flower color (white or purple) and the texture of the peas (smooth or wrinkled). Mendel counted many generations of pea plant offspring and learned that these characteristics were passed on to the next generation in orderly, predictable ratios.
When he cross-bred purple-flowered pea plants with white-flowered ones, the next generation had only purple flowers. But directions for making white flowers were hidden somewhere in the peas of that generation, because when those purple-flowered plants were bred to each other, some of their offspring had white flowers. What's more, the second-generation plants displayed the colors in a predictable pattern. On average, 75 percent of the second-generation plants had purple flowers and 25 percent of the plants had white flowers. Those same ratios persisted, and were reproduced when the experiment was repeated many times over.
Trying to solve the mystery of the missing color blooms, Mendel imagined that the reproductive cells of his pea plants might contain discrete "factors," each of which specified a particular trait, such as white flowers. Mendel reasoned that the factors, whatever they were, must be physical material because they passed from parent to offspring in a mathematically orderly way. It wasn't until many years later, when the other scientists unearthed Mendel's report, that the factors were named genes.
Early geneticists quickly discovered that Mendel's mathematical rules of inheritance applied not just to peas, but also to all plants, animals and people. The discovery of a quantitative rule for inheritance was momentous. It revealed that a common, general principle governed the growth and development of all life on Earth.
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Up until the 1950s, scientists knew a good deal about heredity, but they didn't have a clue what DNA looked like. In order to learn more about DNA and its structure, some scientists experimented with using X rays as a form of molecular photography.
In 1953, Watson and Crick created their historic model of the shape of DNA: the double helix. COLD SPRING HARBOR LABORATORY ARCHIVES
Rosalind Franklin, a physical chemist working with Maurice Wilkins at King's College in London, was among the first to use this method to analyze genetic material. Her experiments produced what were referred to at the time as "the most beautiful X-ray photographs of any substance ever taken."
Other scientists, including zoologist James Watson and physicist Francis Crick, both working at Cambridge University in the United Kingdom, were trying to determine the shape of DNA too. Ultimately, this line of research revealed one of the most profound scientific discoveries of the 20th century: that DNA exists as a double helix.
The 1962 Nobel Prize in physiology or medicine was awarded to Watson, Crick and Wilkins for this work. Although Franklin did not earn a share of the prize due to her untimely death at age 38, she is widely recognized as having played a significant role in the discovery.
Rosalind Franklin's original X-ray diffraction photo revealed the physical structure of DNA. OREGON STATE UNIVERSITY LIBRARIES SPECIAL COLLECTIONS
The spiral staircase-shaped double helix has attained global status as the symbol for DNA. But what is so beautiful about the discovery of the twisting ladder structure isn't just its good looks. Rather, the structure of DNA taught researchers a fundamental lesson about genetics. It taught them that the two connected strandswinding together like parallel handrailswere complementary to each other, and this unlocked the secret of how genetic information is stored, transferred and copied.
In genetics, complementary means that if you know the sequence of nucleotide building blocks on one strand, you know the sequence of nucleotide building blocks on the other strand: A always matches up with T and C always links to G (see drawing).
Long strings of nucleotides form genes, and groups of genes are packaged tightly into structures called chromosomes. Every cell in your body except for eggs, sperm and red blood cells contains a full set of chromosomes in its nucleus.
If the chromosomes in one of your cells were uncoiled and placed end to end, the DNA would be about 6 feet long. If all the DNA in your body were connected in this way, it would stretch approximately 67 billion miles! That's nearly 150,000 round trips to the Moon.
The long, stringy DNA that makes up genes is spooled within chromosomes inside the nucleus of a cell. (Note that a gene would actually be a much longer stretch of DNA than what is shown here.)
DNA consists of two long, twisted chains made up of nucleotides. Each nucleotide contains one base, one phosphate molecule and the sugar molecule deoxyribose. The bases in DNA nucleotides are adenine, thymine, cytosine and guanine.
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Humans have 23 pairs of chromosomes. Male DNA (pictured here) contains an X and a Y chromosome, whereas female DNA contains two X chromosomes. CYTOGENETICS LABORATORY, BRIGHAM AND WOMEN'S HOSPITAL
It's astounding to think that your body consists of trillions of cells. But what's most amazing is that it all starts with one cell. How does this massive expansion take place?
As an embryo progresses through development, its cells must reproduce. But before a cell divides into two new, nearly identical cells, it must copy its DNA so there will be a complete set of genes to pass on to each of the new cells.
To make a copy of itself, the twisted, compacted double helix of DNA has to unwind and separate its two strands. Each strand becomes a pattern, or template, for making a new strand, so the two new DNA molecules have one new strand and one old strand.
The copy is courtesy of a cellular protein machine called DNA polymerase, which reads the template DNA strand and stitches together the complementary new strand. The process, called replication, is astonishingly fast and accurate, although occasional mistakes, such as deletions or duplications, occur. Fortunately, a cellular spell-checker catches and corrects nearly all of these errors.
When DNA polymerase makes an error while copying a gene's DNA sequence, the mistake is called a mutation. In this example, the nucleotide G has been changed to an A.
During DNA replication, each strand of the original molecule acts as a template for the synthesis of a new, complementary DNA strand.
Mistakes that are not corrected can lead to diseases such as cancer and certain genetic disorders. Some of these include Fanconi anemia, early aging diseases and other conditions in which people are extremely sensitive to sunlight and some chemicals.
DNA copying is not the only time when DNA damage can happen. Prolonged, unprotected sun exposure can cause DNA changes that lead to skin cancer, and toxins in cigarette smoke can cause lung cancer.
It may seem ironic, then, that many drugs used to treat cancer work by attacking DNA. That's because these chemotherapy drugs disrupt the DNA copying process, which goes on much faster in rapidly dividing cancer cells than in other cells of the body. The trouble is that most of these drugs do affect normal cells that grow and divide frequently, such as cells of the immune system and hair cells.
Understanding DNA replication better could be a key to limiting a drug's action to cancer cells only.
After copying its DNA, a cell's next challenge is getting just the right amount of genetic material into each of its two offspring.
Most of your cells are called diploid ("di" means two, and "ploid" refers to sets of chromosomes) because they have two sets of chromosomes (23 pairs). Eggs and sperm are different; these are known as haploid cells. Each haploid cell has only one set of 23 chromosomes so that at fertilization the math will work out: A haploid egg cell will combine with a haploid sperm cell to form a diploid cell with the right number of chromosomes: 46.
Chromosomes are numbered 1 to 22, according to size, with 1 being the largest chromosome. The 23rd pair, known as the sex chromosomes, are called X and Y. In humans, abnormalities of chromosome number usually occur during meiosis, the time when a cell reduces its chromosomes from diploid to haploid in creating eggs or sperm.
What happens if an egg or a sperm cell gets the wrong number of chromosomes, and how often does this happen?
Trisomy, the hallmark of Down syndrome, results when a baby is born with three copies of chromosome 21 instead of the usual two.
Molecular biologist Angelika Amon of the Massachusetts Institute of Technology in Cambridge says that mistakes in dividing DNA between daughter cells during meiosis are the leading cause of human birth defects and miscarriages. Current estimates are that 10 percent of all embryos have an incorrect chromosome number. Most of these don't go to full term and are miscarried.
In women, the likelihood that chromosomes won't be apportioned properly increases with age. One of every 18 babies born to women over 45 has three copies of chromosome 13, 18 or 21 instead of the normal two, and this improper balancing can cause trouble. For example, three copies of chromosome 21 lead to Down syndrome.
To make her work easier, Amonlike many other basic scientistsstudies yeast cells, which separate their chromosomes almost exactly the same way human cells do, except that yeast do it much faster. A yeast cell copies its DNA and produces daughter cells in about 1 1/2 hours, compared to a whole day for human cells.
The yeast cells she uses are the same kind bakeries use to make bread and breweries use to make beer!
Amon has made major progress in understanding the details of meiosis. Her research shows how, in healthy cells, gluelike protein complexes called cohesins release pairs of chromosomes at exactly the right time. This allows the chromosomes to separate properly.
These findings have important implications for understanding and treating infertility, birth defects and cancer.
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So, we've described DNAits basic properties and how our bodies make more of it. But how does DNA serve as the language of life? How do you get a protein from a gene?
There are two major steps in making a protein. The first is transcription, where the information coded in DNA is copied into RNA. The RNA nucleotides are complementary to those on the DNA: a C on the RNA strand matches a G on the DNA strand.
1. RNA polymerase transcribes DNA to make messenger RNA (mRNA). 2. The mRNA sequence (dark red strand) is complementary to the DNA sequence (blue strand). 3. On ribosomes, transfer RNA (tRNA) helps convert mRNA into protein. 4. Amino acids link up to make a protein.
The only difference is that RNA pairs a nucleotide called uracil (U), instead of a T, with an A on the DNA.
A protein machine called RNA polymerase reads the DNA and makes the RNA copy. This copy is called messenger RNA, or mRNA, because it delivers the gene's message to the protein-producing machinery.
At this point you may be wondering why all of the cells in the human body aren't exactly alike, since they all contain the same DNA.What makes a liver cell different from a brain cell? How do the cells in the heart make the organ contract, but those in skin allow us to sweat?
Cells can look and act differently, and do entirely different jobs, because each cell "turns on," or expresses, only the genes appropriate for what it needs to do.
RNA polymerase (green) and one end of a DNA strand (blue) are attached to clear beads pinned down in two optical traps. As RNA polymerase moves along the DNA, it creates an RNA copy of a gene, shown here as a pink strand. STEVEN BLOCK
That's because RNA polymerase does not work alone, but rather functions with the aid of many helper proteins. While the core part of RNA polymerase is the same in all cells, the helpers vary in different cell types throughout the body.
You'd think that for a process so essential to life, researchers would know a lot about how transcription works. While it's true that the basics are clearbiologists have been studying gene transcribing by RNA polymerases since these proteins were first discovered in 1960 some of the details are actually still murky.
The biggest obstacle to learning more has been a lack of tools. Until recently, researchers were unable to get a picture at the atomic level of the giant RNA polymerase protein assemblies inside cells to understand how the many pieces of this amazing, living machine do what they do, and do it so well.
But our understanding is improving fast, thanks to spectacular technological advances. We have new X-ray pictures that are far more sophisticated than those that revealed the structure of DNA. Roger Kornberg of Stanford University in California used such methods to determine the structure of RNA polymerase. This work earned him the 2006 Nobel Prize in chemistry. In addition, very powerful microscopes and other tools that allow us to watch one molecule at a time provide a new look at RNA polymerase while it's at work reading DNA and producing RNA.
For example, Steven Block, also of Stanford, has used a physics technique called optical trapping to track RNA polymerase as it inches along DNA. Block and his team performed this work by designing a specialized microscope sensitive enough to watch the real-time motion of a single polymerase traveling down a gene on one chromosome.
The researchers discovered that molecules of RNA polymerase behave like battery-powered spiders as they crawl along the DNA ladder, adding nucleotides one at a time to the growing RNA strand. The enzyme works much like a motor, Block believes, powered by energy released during the chemical synthesis of RNA.
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Genes are often interrupted by stretches of DNA (introns, blue) that do not contain instructions for making a protein. The DNA segments that do contain protein-making instructions are known as exons (green).
Several types of RNA play key roles in making a protein. The gene transcript (the mRNA) transfers information from DNA in the nucleus to the ribosomes that make protein. Ribosomal RNA forms about 60 percent of the ribosomes. Lastly, transfer RNA carries amino acids to the ribosomes. As you can see, all three types of cellular RNAs come together to produce new proteins.
But the journey from gene to protein isn't quite as simple as we've just made it out to be. After transcription, several things need to happen to mRNA before a protein can be made. For example, the genetic material of humans and other eukaryotes (organisms that have a nucleus) includes a lot of DNA that doesn't encode proteins. Some of this DNA is stuck right in the middle of genes.
To distinguish the two types of DNA, scientists call the coding sequences of genes exons and the pieces in between introns (for intervening sequences).
If RNA polymerase were to transcribe DNA from the start of an intron-containing gene to the end, the RNA would be complementary to the introns as well as the exons.
To get an mRNA molecule that yields a working protein, the cell needs to trim out the intron sections and then stitch only the exon pieces together (see drawing). This process is called RNA splicing.
Arranging exons in different patterns, called alternative splicing, enables cells to make different proteins from a single gene.
Splicing has to be extremely accurate. An error in the splicing process, even one that results in the deletion of just one nucleotide in an exon or the addition of just one nucleotide in an intron, will throw the whole sequence out of alignment. The result is usually an abnormal proteinor no protein at all. One form of Alzheimer's disease, for example, is caused by this kind of splicing error.
Molecular biologist Christine Guthrie of the University of California, San Francisco, wants to understand more fully the mechanism for removing intron RNA and find out how it stays so accurate.
She uses yeast cells for these experiments. Just like human DNA, yeast DNA has introns, but they are fewer and simpler in structure and are therefore easier to study. Guthrie can identify which genes are required for splicing by finding abnormal yeast cells that mangle splicing.
So why do introns exist, if they're just going to be chopped out? Without introns, cells wouldn't need to go through the splicing process and keep monitoring it to be sure it's working right.
As it turns out, splicing also makes it possible for cells to create more proteins.
Think about all the exons in a gene. If a cell stitches together exons 1, 2 and 4, leaving out exon 3, the mRNA will specify the production of a particular protein. But instead, if the cell stitches together exons 1, 2 and 3, this time leaving out exon 4, then the mRNA will be translated into a different protein (see drawing).
By cutting and pasting the exons in different patterns, which scientists call alternative splicing, a cell can create different proteins from a single gene. Alternative splicing is one of the reasons why human cells, which have about 20,000 genes, can make hundreds of thousands of different proteins.
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Until recently, researchers looked at genes, and the proteins they encode, one at a time. Now, they can look at how large numbers of genes and proteins act, as well as how they interact. This gives them a much better picture of what goes on in a living organism.
Already, scientists can identify all of the genes that are transcribed in a cellor in an organ, like the heart. And although researchers can't tell you, right now, what's going on in every cell of your body while you read a book or walk down the street, they can do this sort of "whole-body" scan for simpler, single-celled organisms like yeast.
Using a technique called genome-wide location analysis, Richard Young of the Massachusetts Institute of Technology unraveled a "regulatory code" of living yeast cells, which have more than 6,000 genes in their genome. Young's technique enabled him to determine the exact places where RNA polymerase's helper proteins sit on DNA and tell RNA polymerase to begin transcribing a gene.
Since he did the experiment with the yeast exposed to a variety of different conditions,Young was able to figure out how transcription patterns differ when the yeast cell is under stress (say, in a dry environment) or thriving in a sugary-rich nutrient solution. Done one gene at a time, using methods considered state-of-the-art just a few years ago, this kind of analysis would have taken hundreds of years.
After demonstrating that his technique worked in yeast, Young then took his research a step forward. He used a variation of the yeast method to scan the entire human genome in small samples of cells taken from the pancreases and livers of people with type 2 diabetes. He used the results to identify genes that aren't transcribed correctly in people with the disease.
This information provides researchers with an important tool for understanding how diabetes and other diseases are influenced by defective genes. By building models to predict how genes respond in diverse situations, researchers may be able to learn how to stop or jump-start genes on demand, change the course of a disease or prevent it from ever happening.
While most genetic research uses lab organisms, test tubes and petri dishes, the results have real consequences for people. Your first encounter with genetic analysis probably happened shortly after you were born, when a doctor or nurse took a drop of blood from the heel of your tiny foot.
Lab tests performed with that single drop of blood can diagnose certain rare genetic disorders as well as metabolic problems like phenylketonuria (PKU).
Screening newborns in this way began in the 1960s in Massachusetts with testing for PKU, a disease affecting 1 in 14,000 people. PKU is caused by an enzyme that doesn't work properly due to a genetic mutation. Those born with this disorder cannot metabolize the amino acid phenylalanine, which is present in many foods. Left untreated, PKU can lead to mental retardation and neurological damage, but a special diet can prevent these outcomes. Testing for this condition has made a huge difference in many lives.
Newborn screening is governed by individual states. This means that the state in which a baby is born determines the genetic conditions for which he or she will be screened. Currently, states test for between 28 and 54 conditions. All states test for PKU.
Although expanded screening for genetic diseases in newborns is advocated by some, others question the value of screening for conditions that are currently untreatable. Another issue is that some children with mild versions of certain genetic diseases may be treated needlessly.
In 2006, the Advisory Committee on Heritable Disorders in Newborns and Children, which assists the Secretary of the U.S. Department of Health and Human Services, recommended a standard, national set of newborn tests for 29 conditions, ranging from relatively common hearing problems to very rare metabolic diseases.
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A ribosome consists of large and small protein subunits with transfer RNAs nestled in the middle. RIBOSOME STRUCTURE COURTESY OF JAMIE CATE, MARAT YUSUPOV, GULNARA YUSUPOVA, THOMAS EARNEST AND HARRY NOLLER. GRAPHIC COURTESY OF ALBION BAUCOM, UNIVERSITY OF CALIFORNIA, SANTA CRUZ.
After a gene has been read by RNA polymerase and the RNA is spliced, what happens next in the journey from gene to protein? The next step is reading the RNA information and fitting the building blocks of a protein together. This is called translation, and its principal actors are the ribosome and amino acids.
Ribosomes are among the biggest and most intricate structures in the cell. The ribosomes of bacteria contain not only huge amounts of RNA, but also more than 50 different proteins. Human ribosomes have even more RNA and between 70 and 80 different proteins!
Harry Noller of the University of California, Santa Cruz, has found that a ribosome performs several key jobs when it translates the genetic code of mRNA. As the messenger RNA threads through the ribosome protein machine, the ribosome reads the mRNA sequence and helps recognize and recruit the correct amino acid-carrying transfer RNA to match the mRNA code. The ribosome also links each additional amino acid into a growing protein chain (see drawing).
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DNA repair – Wikipedia, the free encyclopedia
Posted: September 8, 2016 at 6:32 am
DNA damage resulting in multiple broken chromosomes
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day.[1] Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages (interstrand crosslinks or ICLs).[2][3] This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.
The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:
The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection.[4]
The 2015 Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich, and Aziz Sancar for their work on the molecular mechanisms of DNA repair processes.[5][6]
DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day.[1] While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation and contribute to tumour heterogeneity.
The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules' regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA, DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, supercoiled and wound around "packaging" proteins called histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.
DNA damage can be subdivided into two main types:
The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is unrecoverable (except in the rare case of a back mutation, for example, through gene conversion).
There are several types of damage to DNA due to endogenous cellular processes:
Damage caused by exogenous agents comes in many forms. Some examples are:
UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift.
In human cells, and eukaryotic cells in general, DNA is found in two cellular locations inside the nucleus and inside the mitochondria. Nuclear DNA (nDNA) exists as chromatin during non-replicative stages of the cell cycle and is condensed into aggregate structures known as chromosomes during cell division. In either state the DNA is highly compacted and wound up around bead-like proteins called histones. Whenever a cell needs to express the genetic information encoded in its nDNA the required chromosomal region is unravelled, genes located therein are expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria organelles, exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, reactive oxygen species (ROS), or free radicals, byproducts of the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation, create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the toxicity of these species is superoxide dismutase, which is present in both the mitochondria and cytoplasm of eukaryotic cells.
Senescence, an irreversible process in which the cell no longer divides, is a protective response to the shortening of the chromosome ends. The telomeres are long regions of repetitive noncoding DNA that cap chromosomes and undergo partial degradation each time a cell undergoes division (see Hayflick limit).[10] In contrast, quiescence is a reversible state of cellular dormancy that is unrelated to genome damage (see cell cycle). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism,[11] which serves as a "last resort" mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth cellular signaling. Unregulated cell division can lead to the formation of a tumor (see cancer), which is potentially lethal to an organism. Therefore, the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.[12]
It is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damages and mutation are fundamentally different. Damages are physical abnormalities in the DNA, such as single- and double-strand breaks, 8-hydroxydeoxyguanosine residues, and polycyclic aromatic hydrocarbon adducts. DNA damages can be recognized by enzymes, and, thus, they can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented, and, thus, translation into a protein will also be blocked. Replication may also be blocked or the cell may die.
In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and, thus, a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair; these errors are a major source of mutation.
Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell's survival. Thus, in a population of cells composing a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus, DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging.[13]
Single-strand and double-strand DNA damage
Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome (but cells remain superficially functional when non-essential genes are missing or damaged). Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.
Damage to DNA alters the spatial configuration of the helix, and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place.
Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can occur in only one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone. The formation of pyrimidine dimers upon irradiation with UV light results in an abnormal covalent bond between adjacent pyrimidine bases. The photoreactivation process directly reverses this damage by the action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed from blue/UV light (300500nm wavelength) to promote catalysis.[14] Photolyase, an old enzyme present in bacteria, fungi, and most animals no longer functions in humans,[15] who instead use nucleotide excision repair to repair damage from UV irradiation. Another type of damage, methylation of guanine bases, is directly reversed by the protein methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called ogt. This is an expensive process because each MGMT molecule can be used only once; that is, the reaction is stoichiometric rather than catalytic.[16] A generalized response to methylating agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes.[17] The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.
When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand.[16]
Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Three mechanisms exist to repair double-strand breaks (DSBs): non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination.[16] PVN Acharya noted that double-strand breaks and a "cross-linkage joining both strands at the same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next mitosis or in some rare instances, mutate."[2][3]
In NHEJ, DNA Ligase IV, a specialized DNA ligase that forms a complex with the cofactor XRCC4, directly joins the two ends.[21] To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate.[22][23][24][25] NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms insertions or translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are "backup" NHEJ pathways in higher eukaryotes.[26] Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.[27]
MMEJ starts with short-range end resection by MRE11 nuclease on either side of a double-strand break to reveal microhomology regions.[28] In further steps,[29] PARP1 is required and may be an early step in MMEJ. There is pairing of microhomology regions followed by recruitment of flap structure-specific endonuclease 1 (FEN1) to remove overhanging flaps. This is followed by recruitment of XRCC1LIG3 to the site for ligating the DNA ends, leading to an intact DNA.
DNA double strand breaks in mammalian cells are primarily repaired by homologous recombination (HR) and non-homologous end joining (NHEJ).[30] In an in vitro system, MMEJ occurred in mammalian cells at the levels of 1020% of HR when both HR and NHEJ mechanisms were also available.[28] MMEJ is always accompanied by a deletion, so that MMEJ is a mutagenic pathway for DNA repair.[31]
Homologous recombination requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.
Topoisomerases introduce both single- and double-strand breaks in the course of changing the DNA's state of supercoiling, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.
A team of French researchers bombarded Deinococcus radiodurans to study the mechanism of double-strand break DNA repair in that bacterium. At least two copies of the genome, with random DNA breaks, can form DNA fragments through annealing. Partially overlapping fragments are then used for synthesis of homologous regions through a moving D-loop that can continue extension until they find complementary partner strands. In the final step there is crossover by means of RecA-dependent homologous recombination.[32]
Translesion synthesis (TLS) is a DNA damage tolerance process that allows the DNA replication machinery to replicate past DNA lesions such as thymine dimers or AP sites.[33] It involves switching out regular DNA polymerases for specialized translesion polymerases (i.e. DNA polymerase IV or V, from the Y Polymerase family), often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication processivity factor PCNA. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) on undamaged templates relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, Pol mediates error-free bypass of lesions induced by UV irradiation, whereas Pol introduces mutations at these sites. Pol is known to add the first adenine across the T^T photodimer using Watson-Crick base pairing and the second adenine will be added in its syn conformation using Hoogsteen base pairing. From a cellular perspective, risking the introduction of point mutations during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death. In short, the process involves specialized polymerases either bypassing or repairing lesions at locations of stalled DNA replication. For example, Human DNA polymerase eta can bypass complex DNA lesions like guanine-thymine intra-strand crosslink, G[8,5-Me]T, although can cause targeted and semi-targeted mutations.[34] Paromita Raychaudhury and Ashis Basu[35] studied the toxicity and mutagenesis of the same lesion in Escherichia coli by replicating a G[8,5-Me]T-modified plasmid in E. coli with specific DNA polymerase knockouts. Viability was very low in a strain lacking pol II, pol IV, and pol V, the three SOS-inducible DNA polymerases, indicating that translesion synthesis is conducted primarily by these specialized DNA polymerases. A bypass platform is provided to these polymerases by Proliferating cell nuclear antigen (PCNA). Under normal circumstances, PCNA bound to polymerases replicates the DNA. At a site of lesion, PCNA is ubiquitinated, or modified, by the RAD6/RAD18 proteins to provide a platform for the specialized polymerases to bypass the lesion and resume DNA replication.[36][37] After translesion synthesis, extension is required. This extension can be carried out by a replicative polymerase if the TLS is error-free, as in the case of Pol , yet if TLS results in a mismatch, a specialized polymerase is needed to extend it; Pol . Pol is unique in that it can extend terminal mismatches, whereas more processive polymerases cannot. So when a lesion is encountered, the replication fork will stall, PCNA will switch from a processive polymerase to a TLS polymerase such as Pol to fix the lesion, then PCNA may switch to Pol to extend the mismatch, and last PCNA will switch to the processive polymerase to continue replication.
Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions and double-strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins, carbohydrates, lipids, and RNA. The accumulation of damage, to be specific, double-strand breaks or adducts stalling the replication forks, are among known stimulation signals for a global response to DNA damage.[38] The global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance, or apoptosis. The common features of global response are induction of multiple genes, cell cycle arrest, and inhibition of cell division.
After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure,[39] whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified.[40] These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.
DNA damage checkpoint is a signal transduction pathway that blocks cell cycle progression in G1, G2 and metaphase and slows down the rate of S phase progression when DNA is damaged. It leads to a pause in cell cycle allowing the cell time to repair the damage before continuing to divide.
Checkpoint Proteins can be separated into four groups: phosphatidylinositol 3-kinase (PI3K)-like protein kinase, proliferating cell nuclear antigen (PCNA)-like group, two serine/threonine(S/T) kinases and their adaptors. Central to all DNA damage induced checkpoints responses is a pair of large protein kinases belonging to the first group of PI3K-like protein kinases-the ATM (Ataxia telangiectasia mutated) and ATR (Ataxia- and Rad-related) kinases, whose sequence and functions have been well conserved in evolution. All DNA damage response requires either ATM or ATR because they have the ability to bind to the chromosomes at the site of DNA damage, together with accessory proteins that are platforms on which DNA damage response components and DNA repair complexes can be assembled.
An important downstream target of ATM and ATR is p53, as it is required for inducing apoptosis following DNA damage.[41] The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and p53-independent mechanisms and can arrest the cell cycle at the G1/S and G2/M checkpoints by deactivating cyclin/cyclin-dependent kinase complexes.[42]
The SOS response is the changes in gene expression in Escherichia coli and other bacteria in response to extensive DNA damage. The prokaryotic SOS system is regulated by two key proteins: LexA and RecA. The LexA homodimer is a transcriptional repressor that binds to operator sequences commonly referred to as SOS boxes. In Escherichia coli it is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes.[43] The SOS response is known to be widespread in the Bacteria domain, but it is mostly absent in some bacterial phyla, like the Spirochetes.[44] The most common cellular signals activating the SOS response are regions of single-stranded DNA (ssDNA), arising from stalled replication forks or double-strand breaks, which are processed by DNA helicase to separate the two DNA strands.[38] In the initiation step, RecA protein binds to ssDNA in an ATP hydrolysis driven reaction creating RecAssDNA filaments. RecAssDNA filaments activate LexA autoprotease activity, which ultimately leads to cleavage of LexA dimer and subsequent LexA degradation. The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition of cell division and an increase in levels of proteins responsible for damage processing.
In Escherichia coli, SOS boxes are 20-nucleotide long sequences near promoters with palindromic structure and a high degree of sequence conservation. In other classes and phyla, the sequence of SOS boxes varies considerably, with different length and composition, but it is always highly conserved and one of the strongest short signals in the genome.[44] The high information content of SOS boxes permits differential binding of LexA to different promoters and allows for timing of the SOS response. The lesion repair genes are induced at the beginning of SOS response. The error-prone translesion polymerases, for example, UmuCD'2 (also called DNA polymerase V), are induced later on as a last resort.[45] Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer, which then binds to the SOS boxes near promoters and restores normal gene expression.
Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental shock response indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are distributed among different organs that have evolved different sensitivities to DNA damage.[46]
In general global response to DNA damage involves expression of multiple genes responsible for postreplication repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional activation, genes controlling mRNA decay, and many others. A large amount of damage to a cell leaves it with an important decision: undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival that will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase are members of [Y family translesion DNA polymerases present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes.[38]
DNA repair rate is an important determinant of cell pathology
Experimental animals with genetic deficiencies in DNA repair often show decreased life span and increased cancer incidence.[13] For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get lymphoma and infections more often, and, as a consequence, have shorter lifespans than wild-type mice.[47] In similar manner, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan.[48] However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened life span without correspondingly higher rates of mutation.[49]
If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis, or cancer. Inherited diseases associated with faulty DNA repair functioning result in premature aging,[13] increased sensitivity to carcinogens, and correspondingly increased cancer risk (see below). On the other hand, organisms with enhanced DNA repair systems, such as Deinococcus radiodurans, the most radiation-resistant known organism, exhibit remarkable resistance to the double-strand break-inducing effects of radioactivity, likely due to enhanced efficiency of DNA repair and especially NHEJ.[50]
Most life span influencing genes affect the rate of DNA damage
A number of individual genes have been identified as influencing variations in life span within a population of organisms. The effects of these genes is strongly dependent on the environment, in particular, on the organism's diet. Caloric restriction reproducibly results in extended lifespan in a variety of organisms, likely via nutrient sensing pathways and decreased metabolic rate. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see[51] for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction.
For example, increasing the gene dosage of the gene SIR-2, which regulates DNA packaging in the nematode worm Caenorhabditis elegans, can significantly extend lifespan.[52] The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction.[53] Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents,[54] although similar effects have not been observed in mitochondrial DNA.[55]
The C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended life span under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction.[56] This observation supports the pleiotropy theory of the biological origins of aging, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life.
Defects in the NER mechanism are responsible for several genetic disorders, including:
Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.
Other DNA repair disorders include:
All of the above diseases are often called "segmental progerias" ("accelerated aging diseases") because their victims appear elderly and suffer from aging-related diseases at an abnormally young age, while not manifesting all the symptoms of old age.
Other diseases associated with reduced DNA repair function include Fanconi anemia, hereditary breast cancer and hereditary colon cancer.
Because of inherent limitations in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer.[57][58] There are at least 34 Inherited human DNA repair gene mutations that increase cancer risk. Many of these mutations cause DNA repair to be less effective than normal. In particular, Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. BRCA1 and BRCA2, two famous genes whose mutations confer a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination.
Cancer therapy procedures such as chemotherapy and radiotherapy work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing most typically cancer cells are preferentially affected. The side-effect is that other non-cancerous but rapidly dividing cells such as progenitor cells in the gut, skin, and hematopoietic system are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body).
Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomal aberrations. However, it has become apparent that cancer is also driven by epigenetic alterations.[59]
Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification,[60] changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1)[61] and changes caused by microRNAs. Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes usually remain through cell divisions, last for multiple cell generations, and can be considered to be epimutations (equivalent to mutations).
While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, appear to be particularly important. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.[62][63][64][65]
Reduced expression of DNA repair genes causes deficient DNA repair. When DNA repair is deficient DNA damages remain in cells at a higher than usual level and these excess damages cause increased frequencies of mutation or epimutation. Mutation rates increase substantially in cells defective in DNA mismatch repair[66][67] or in homologous recombinational repair (HRR).[68] Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.[69]
Higher levels of DNA damage not only cause increased mutation, but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.[70][71]
Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations).[72] However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.[73]
Deficiencies in DNA repair enzymes are occasionally caused by a newly arising somatic mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. For example, when 113 colorectal cancers were examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).[74] Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.[75][76][77][78][79]
Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[80] In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.[81]
In further examples (tabulated in Table 4 of this reference[82]), epigenetic defects were found at frequencies of between 13%-100% for the DNA repair genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM. These epigenetic defects occurred in various cancers (e.g. breast, ovarian, colorectal and head and neck). Two or three deficiencies in the expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.[83]
The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes.[84] Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart.
Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Wikipedia articles on each of the genes high-lighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Two review articles,[82][85] and two broad experimental survey articles[86][87] also document most of these epigenetic DNA repair deficiencies in cancers.
Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. When these genes have low or absent expression, DNA damages can accumulate. Replication errors past these damages (see translesion synthesis) can lead to increased mutations and, ultimately, cancer. Epigenetic repression of DNA repair genes in accurate DNA repair pathways appear to be central to carcinogenesis.
The two gray-highlighted genes RAD51 and BRCA2, are required for homologous recombinational repair. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers. As indicated in the Wikipedia articles on RAD51 and BRCA2, such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. These repair deficiencies would likely cause increased unrepaired DNA damages. The over-expression of RAD51 and BRCA2 seen in these cancers may reflect selective pressures for compensatory RAD51 or BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In those cases where RAD51 or BRCA2 are under-expressed, this would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis) could cause increased mutations and cancer, so that under-expression of RAD51 or BRCA2 would be carcinogenic in itself.
Cyan-highlighted genes are in the microhomology-mediated end joining (MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone inaccurate repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5-25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates the strands to create an intact DNA double helix. MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway.[88]FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast,[89] prostate,[90] stomach,[91][92] neuroblastomas,[93] pancreas,[94] and lung.[95] PARP1 is also over-expressed when its promoter region ETS site is epigenetically hypomethylated, and this contributes to progression to endometrial cancer,[96] BRCA-mutated ovarian cancer,[97] and BRCA-mutated serous ovarian cancer.[98] Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are also shown in cyan.
The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among bacteriophage (viruses that infect bacteria); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms.[99] The ability of a large number of protein structural motifs to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.[100]
The fossil record indicates that single-cell life began to proliferate on the planet at some point during the Precambrian period, although exactly when recognizably modern life first emerged is unclear. Nucleic acids became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earth's oxygen-rich atmosphere (known as the "oxygen catastrophe") due to photosynthetic organisms, as well as the presence of potentially damaging free radicals in the cell due to oxidative phosphorylation, necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by oxidative stress.
On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism that results in a change from the original sequence. When this occurs, mutations may propagate into the genomes of the cell's progeny. Should such an event occur in a germ line cell that will eventually produce a gamete, the mutation has the potential to be passed on to the organism's offspring. The rate of evolution in a particular species (or, in a particular gene) is a function of the rate of mutation. As a consequence, the rate and accuracy of DNA repair mechanisms have an influence over the process of evolutionary change.[101] Since the normal adaptation of populations of organisms to changing circumstances (for instance the adaptation of the beaks of a population of finches to the changing presence of hard seeds or insects) proceeds by gene regulation and the recombination and selection of gene variations alleles and not by passing on irreparable DNA damages to the offspring,[102] DNA damage protection and repair does not influence the rate of adaptation by gene regulation and by recombination and selection of alleles. On the other hand, DNA damage repair and protection does influence the rate of accumulation of irreparable, advantageous, code expanding, inheritable mutations, and slows down the evolutionary mechanism for expansion of the genome of organisms with new functionalities. The tension between evolvability and mutation repair and protection needs further investigation.
A technology named clustered regularly interspaced short palindromic repeat shortened to CRISPR-Cas9 was discovered in 2012. The new technology allows anyone with molecular biology training to alter the genes of any species with precision.[103]
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Nucleic acid double helix – Wikipedia, the free encyclopedia
Posted: August 23, 2016 at 9:19 am
In molecular biology, the term double helix[1] refers to the structure formed by double-stranded molecules of nucleic acids such as DNA. The double helical structure of a nucleic acid complex arises as a consequence of its secondary structure, and is a fundamental component in determining its tertiary structure. The term entered popular culture with the publication in 1968 of The Double Helix: A Personal Account of the Discovery of the Structure of DNA, by James Watson.
The DNA double helix polymer of nucleic acid, held together by nucleotides which base pair together.[2] In B-DNA, the most common double helical structure found in nature, the double helix is right-handed with about 1010.5 base pairs per turn.[3] This translates into about 20-21 nucleotides per turn. The double helix structure of DNA contains a major groove and minor groove. In B-DNA the major groove is wider than the minor groove.[2] Given the difference in widths of the major groove and minor groove, many proteins which bind to B-DNA do so through the wider major groove.[4]
The double-helix model of DNA structure was first published in the journal Nature by James D. Watson and Francis Crick in 1953,[5] (X,Y,Z coordinates in 1954[6]) based upon the crucial X-ray diffraction image of DNA labeled as "Photo 51", from Rosalind Franklin in 1952,[7] followed by her more clarified DNA image with Raymond Gosling,[8][9]Maurice Wilkins, Alexander Stokes, and Herbert Wilson,[10] as well as base-pairing chemical and biochemical information by Erwin Chargaff.[11][12][13][14][15][16] The previous model was triple-stranded DNA.[17]
The realization that the structure of DNA is that of a double-helix elucidated the mechanism of base pairing by which genetic information is stored and copied in living organisms and is widely considered one of the most important scientific discoveries of the 20th century. Crick, Wilkins, and Watson each received one third of the 1962 Nobel Prize in Physiology or Medicine for their contributions to the discovery.[18] (Franklin, whose breakthrough X-ray diffraction data was used to formulate the DNA structure, died in 1958, and thus was ineligible to be nominated for a Nobel Prize.)
Hybridization is the process of complementary base pairs binding to form a double helix. Melting is the process by which the interactions between the strands of the double helix are broken, separating the two nucleic acid strands. These bonds are weak, easily separated by gentle heating, enzymes, or physical force. Melting occurs preferentially at certain points in the nucleic acid.[19]T and A rich sequences are more easily melted than C and G rich regions. Particular base steps are also susceptible to DNA melting, particularly T A and T G base steps.[20] These mechanical features are reflected by the use of sequences such as TATA at the start of many genes to assist RNA polymerase in melting the DNA for transcription.
Strand separation by gentle heating, as used in PCR, is simple, providing the molecules have fewer than about 10,000 base pairs (10 kilobase pairs, or 10 kbp). The intertwining of the DNA strands makes long segments difficult to separate. The cell avoids this problem by allowing its DNA-melting enzymes (helicases) to work concurrently with topoisomerases, which can chemically cleave the phosphate backbone of one of the strands so that it can swivel around the other. Helicases unwind the strands to facilitate the advance of sequence-reading enzymes such as DNA polymerase.
The geometry of a base, or base pair step can be characterized by 6 coordinates: Shift, slide, rise, tilt, roll, and twist. These values precisely define the location and orientation in space of every base or base pair in a nucleic acid molecule relative to its predecessor along the axis of the helix. Together, they characterize the helical structure of the molecule. In regions of DNA or RNA where the "normal" structure is disrupted, the change in these values can be used to describe such disruption.
For each base pair, considered relative to its predecessor, there are the following base pair geometries to consider:[21][22][23]
Rise and twist determine the handedness and pitch of the helix. The other coordinates, by contrast, can be zero. Slide and shift are typically small in B-DNA, but are substantial in A- and Z-DNA. Roll and tilt make successive base pairs less parallel, and are typically small.
Note that "tilt" has often been used differently in the scientific literature, referring to the deviation of the first, inter-strand base-pair axis from perpendicularity to the helix axis. This corresponds to slide between a succession of base pairs, and in helix-based coordinates is properly termed "inclination".
At least three DNA conformations are believed to be found in nature, A-DNA, B-DNA, and Z-DNA. The "B" form described by James D. Watson and Francis Crick is believed to predominate in cells.[24] It is 23.7 wide and extends 34 per 10 bp of sequence. The double helix makes one complete turn about its axis every 10.4-10.5 base pairs in solution. This frequency of twist (known as the helical pitch) depends largely on stacking forces that each base exerts on its neighbours in the chain. The absolute configuration of the bases determines the direction of the helical curve for a given conformation.
A-DNA and Z-DNA differ significantly in their geometry and dimensions to B-DNA, although still form helical structures. It was long thought that the A form only occurs in dehydrated samples of DNA in the laboratory, such as those used in crystallographic experiments, and in hybrid pairings of DNA and RNA strands, but DNA dehydration does occur in vivo, and A-DNA is now known to have biological functions. Segments of DNA that cells have been methylated for regulatory purposes may adopt the Z geometry, in which the strands turn about the helical axis the opposite way to A-DNA and B-DNA. There is also evidence of protein-DNA complexes forming Z-DNA structures.
Other conformations are possible; A-DNA, B-DNA, C-DNA, E-DNA,[25]L-DNA (the enantiomeric form of D-DNA),[26] P-DNA,[27] S-DNA, Z-DNA, etc. have been described so far.[28] In fact, only the letters F, Q, U, V, and Y are now[update] available to describe any new DNA structure that may appear in the future.[29][30] However, most of these forms have been created synthetically and have not been observed in naturally occurring biological systems.[citation needed] There are also triple-stranded DNA forms and quadruplex forms such as the G-quadruplex.
Twin helical strands form the DNA backbone. Another double helix may be found by tracing the spaces, or grooves, between the strands. These voids are adjacent to the base pairs and may provide a binding site. As the strands are not directly opposite each other, the grooves are unequally sized. One groove, the major groove, is 22 wide and the other, the minor groove, is 12 wide.[34] The narrowness of the minor groove means that the edges of the bases are more accessible in the major groove. As a result, proteins like transcription factors that can bind to specific sequences in double-stranded DNA usually make contacts to the sides of the bases exposed in the major groove.[4] This situation varies in unusual conformations of DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in size that would be seen if the DNA is twisted back into the ordinary B form.
Alternative non-helical models were briefly considered in the late 1970s as a potential solution to problems in the replication of DNA in plasmids and chromatin. However, the models were set aside in favor of the double-helical model due to subsequent experimental advances such as X-ray crystallography of DNA duplexes and later the nucleosome core particle, as well as the discovery of topoisomerases, and these non-double-helical models are not currently accepted by the mainstream scientific community.[35][36]
Single-stranded nucleic acids do not adopt a helical formation, and are described by models such as the random coil or worm-like chain.[citation needed]
DNA is a relatively rigid polymer, typically modelled as a worm-like chain. It has three significant degrees of freedom; bending, twisting and compression, each of which cause particular limitations on what is possible with DNA within a cell. Twisting/torsional stiffness is important for the circularisation of DNA and the orientation of DNA bound proteins relative to each other and bending/axial stiffness is important for DNA wrapping and circularisation and protein interactions. Compression/extension is relatively unimportant in the absence of high tension.
DNA in solution does not take a rigid structure but is continually changing conformation due to thermal vibration and collisions with water molecules, which makes classical measures of rigidity impossible. Hence, the bending stiffness of DNA is measured by the persistence length, defined as:
This value may be directly measured using an atomic force microscope to directly image DNA molecules of various lengths. In an aqueous solution, the average persistence length is 46-50nm or 140-150 base pairs (the diameter of DNA is 2nm), although can vary significantly. This makes DNA a moderately stiff molecule.
The persistence length of a section of DNA is somewhat dependent on its sequence, and this can cause significant variation. The variation is largely due to base stacking energies and the residues which extend into the minor and major grooves.
The entropic flexibility of DNA is remarkably consistent with standard polymer physics models, such as the Kratky-Porod worm-like chain model.[citation needed] Consistent with the worm-like chain model is the observation that bending DNA is also described by Hooke's law at very small (sub-piconewton) forces. However, for DNA segments less than the persistence length, the bending force is approximately constant and behaviour deviates from the worm-like chain predictions.
This effect results in unusual ease in circularising small DNA molecules and a higher probability of finding highly bent sections of DNA.[citation needed]
DNA molecules often have a preferred direction to bend, i.e. anisotropic bending. This is, again, due to the properties of the bases which make up the DNA sequence - a random sequence will have no preferred bend direction, i.e. isotropic bending.
Preferred DNA bend direction is determined by the stability of stacking each base on top of the next. If unstable base stacking steps are always found on one side of the DNA helix then the DNA will preferentially bend away from that direction. As bend angle increases then steric hindrances and ability to roll the residues relative to each other also play a role, especially in the minor groove. A and T residues will be preferentially be found in the minor grooves on the inside of bends. This effect is particularly seen in DNA-protein binding where tight DNA bending is induced, such as in nucleosome particles. See base step distortions above.
DNA molecules with exceptional bending preference can become intrinsically bent. This was first observed in trypanosomatid kinetoplast DNA. Typical sequences which cause this contain stretches of 4-6 T and A residues separated by G and C rich sections which keep the A and T residues in phase with the minor groove on one side of the molecule. For example:
The intrinsically bent structure is induced by the 'propeller twist' of base pairs relative to each other allowing unusual bifurcated Hydrogen-bonds between base steps. At higher temperatures this structure, and so the intrinsic bend, is lost.
All DNA which bends anisotropically has, on average, a longer persistence length and greater axial stiffness. This increased rigidity is required to prevent random bending which would make the molecule act isotropically.
DNA circularization depends on both the axial (bending) stiffness and torsional (rotational) stiffness of the molecule. For a DNA molecule to successfully circularize it must be long enough to easily bend into the full circle and must have the correct number of bases so the ends are in the correct rotation to allow bonding to occur. The optimum length for circularization of DNA is around 400 base pairs (136nm), with an integral number of turns of the DNA helix, i.e. multiples of 10.4 base pairs. Having a non integral number of turns presents a significant energy barrier for circularization, for example a 10.4 x 30 = 312 base pair molecule will circularize hundreds of times faster than 10.4 x 30.5 317 base pair molecule.[38]
Longer stretches of DNA are entropically elastic under tension. When DNA is in solution, it undergoes continuous structural variations due to the energy available in the thermal bath of the solvent. This is due to the thermal vibration of the molecule combined with continual collisions with water molecules. For entropic reasons, more compact relaxed states are thermally accessible than stretched out states, and so DNA molecules are almost universally found in a tangled relaxed layouts. For this reason, a single molecule of DNA will stretch under a force, straightening it out. Using optical tweezers, the entropic stretching behavior of DNA has been studied and analyzed from a polymer physics perspective, and it has been found that DNA behaves largely like the Kratky-Porod worm-like chain model under physiologically accessible energy scales.
Under sufficient tension and positive torque, DNA is thought to undergo a phase transition with the bases splaying outwards and the phosphates moving to the middle. This proposed structure for overstretched DNA has been called "P-form DNA", in honor of Linus Pauling who originally presented it as a possible structure of DNA.[27]
The mechanical properties of DNA under compression have not been characterized due to experimental difficulties in preventing the polymer from bending under the compressive force.[citation needed]
The B form of the DNA helix twists 360 per 10.4-10.5 bp in the absence of torsional strain. But many molecular biological processes can induce torsional strain. A DNA segment with excess or insufficient helical twisting is referred to, respectively, as positively or negatively "supercoiled". DNA in vivo is typically negatively supercoiled, which facilitates the unwinding (melting) of the double-helix required for RNA transcription.
Within the cell most DNA is topologically restricted. DNA is typically found in closed loops (such as plasmids in prokaryotes) which are topologically closed, or as very long molecules whose diffusion coefficients produce effectively topologically closed domains. Linear sections of DNA are also commonly bound to proteins or physical structures (such as membranes) to form closed topological loops.
Francis Crick was one of the first to propose the importance of linking numbers when considering DNA supercoils. In a paper published in 1976, Crick outlined the problem as follows:
In considering supercoils formed by closed double-stranded molecules of DNA certain mathematical concepts, such as the linking number and the twist, are needed. The meaning of these for a closed ribbon is explained and also that of the writhing number of a closed curve. Some simple examples are given, some of which may be relevant to the structure of chromatin.[39]
Analysis of DNA topology uses three values:
Any change of T in a closed topological domain must be balanced by a change in W, and vice versa. This results in higher order structure of DNA. A circular DNA molecule with a writhe of 0 will be circular. If the twist of this molecule is subsequently increased or decreased by supercoiling then the writhe will be appropriately altered, making the molecule undergo plectonemic or toroidal superhelical coiling.
When the ends of a piece of double stranded helical DNA are joined so that it forms a circle the strands are topologically knotted. This means the single strands cannot be separated any process that does not involve breaking a strand (such as heating). The task of un-knotting topologically linked strands of DNA falls to enzymes known as topoisomerases. These enzymes are dedicated to un-knotting circular DNA by cleaving one or both strands so that another double or single stranded segment can pass through. This un-knotting is required for the replication of circular DNA and various types of recombination in linear DNA which have similar topological constraints.
For many years, the origin of residual supercoiling in eukaryotic genomes remained unclear. This topological puzzle was referred to by some as the "linking number paradox".[40] However, when experimentally determined structures of the nucleosome displayed an over-twisted left-handed wrap of DNA around the histone octamer,[41][42] this "paradox" was considered to be solved by the scientific community.
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