Daily Archives: August 2, 2017

August 2, 2017 by David Salisbury Molecular model of the lesion that the bacterial toxin yatakemycin forms on DNA. Credit: Elwood Mullins / Vanderbilt

One of the most potent toxins known acts by welding the two strands of the famous double helix together in a unique fashion which foils the standard repair mechanisms cells use to protect their DNA.

A team of Vanderbilt University researchers have worked out the molecular details that explain how this bacterial toxinyatakemycin (YTM)prevents DNA replication. Their results, described in a paper published online July 24 by Nature Chemical Biology, explain YTM's extraordinary toxicity and could be used to fine-tune the compound's impressive antimicrobial and antifungal properties.

YTM is produced by some members of the Streptomyces family of soil bacteria to kill competing strains of bacteria. It belongs to a class of bacterial compounds that are currently being tested for cancer chemotherapy because their toxicity is extremely effective against tumor cells.

"In the past, we have thought about DNA repair in terms of protecting DNA against different kinds of chemical insults," said Professor of Biological Sciences Brandt Eichman. "Now, toxins like YTM are forcing us to consider their role as part of the ongoing chemical warfare that exists among bacteria, which can have important side effects on human health."

Cells have developed several basic types of DNA repair, including base excision repair (BER) and nucleotide excision repair (NER). BER generally fixes small lesions and NER removes large, bulky lesions.

A number of DNA toxins create bulky lesions that destabilize the double helix. However, some of the most toxic lesions bond to both strands of DNA, thereby preventing the cell's elaborate replication machinery from separating the DNA strands so they can be copied. Normally, this distorts the DNA's structure, which allows NER enzymes to locate the lesion and excise it.

"YTM is different," said postdoctoral fellow Elwood Mullins. "Instead of attaching to DNA with multiple strong covalent bonds, it forms a single covalent bond and a large number of weaker, polar interactions. As a result, it stabilizes the DNA instead of destabilizing it, and it does so without distorting the DNA structure so NER enzymes can't find it."

"We were shocked by how much it stabilizes DNA," Eichman added. "Normally, the DNA strands that we used in our experiments separate when they are heated to about 40 degrees [Celsius] but, with YTM added, they don't come apart until 85 degrees."

The Streptomyces bacteria that produce YTM have also evolved a special enzyme to protect their own DNA from the toxin. Surprisingly, this is a base excision repair enzymecalled a DNA glycosylasethat is normally limited to repairing small lesions, not the bulky adducts caused by YTM. Nevertheless, studies have shown that it is extremely effective.

It so happens that one of Streptomyces' competitors, Bacillus cereus, has managed to co-opt the gene that produces this particular enzyme. In Bacillus, however, the enzyme it producescalled AlkDprovides only limited protection.

In 2015, Eichman and Mullins reported that, unlike other BER enzymes, AlkD can detect and excise YTM lesions. At the time, they had no idea why it wasn't as effective as its Streptomyces counterpart. Now they do. It turns out that AlkD tightly binds the product that it forms from a YTM lesion, inhibiting the downstream steps in the BER process that are necessary to fully return the DNA to its original, undamaged state. This drastically reduces the effectiveness of the repair process as a whole.

In recent years, biologists have discovered that animals and plants host thousands of different species of commensal bacteria and this microscopic community, called the microbiome, plays a surprisingly important role in their health and well-being. Normally, these bacteria are beneficialfor example, converting indigestible foods into digestible formsbut they can also cause problems, such as the stomach bacteria Heliobacter pylori that can cause inflammation that produces ulcers.

"We know that bacteria produce compounds like YTM when they are under stress," Eichman observed. "The negative effects this has on their hosts is an unfortunate side effect. So it is very important that we learn as much as we can about how these bacterial toxins work and how bacteria defend against them."

Explore further: New class of DNA repair enzyme discovered

More information: Elwood A Mullins et al. Toxicity and repair of DNA adducts produced by the natural product yatakemycin, Nature Chemical Biology (2017). DOI: 10.1038/nchembio.2439

This year's Nobel Prize in chemistry was given to three scientists who each focused on one piece of the DNA repair puzzle. Now a new study, reported online Oct. 28 in the journal Nature, reports the discovery of a new class ...

Tucked within its double-helix structure, DNA contains the chemical blueprint that guides all the processes that take place within the cell and are essential for life. Therefore, repairing damage and maintaining the integrity ...

Day in and day out, in our bodies, the DNA in cells is damaged for a variety of reasons, and thus intercellular DNA-repair systems are fundamental to the maintenance of life. Now scientists from the UNC School of Medicine ...

All cells are confronted with DNA damage, for example by exposure of the skin to UV rays, chemical byproducts of nerve cells consuming sugar, or immune cells destroying bacteria. If these DNA lesions are not - or badly - ...

Every day our bodies come under a barrage of toxic agents cigarette smoke, the sun, free radicals and other carcinogenic substances that create damaging lesions in our DNA that can initiate cancer and other human ...

Food poisoning caused by Bacillus cereus can lead to diarrhea which is probably caused by a 3-component toxin which is produced by this bacteria strain and which perforates and kills cells.

One of the most potent toxins known acts by welding the two strands of the famous double helix together in a unique fashion which foils the standard repair mechanisms cells use to protect their DNA.

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Unlike the rigid plastic models from chemistry class, real chains of molecules can bend and stretch, like beads on an elastic cord. Some polymers, like DNA, are especially stretchy, a characteristic that can complicate attempts ...

By some estimates, bacterial strains resistant to antibioticsso-called superbugs - will cause more deaths than cancer by 2050.

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Deciphering potent DNA toxin's secrets - Phys.Org

It's now cheaper than ever to map the human genome. But most healthy people don't seem to care all that much about their DNA.

A startup called Helix is trying to change that. The company launches this month with more than a dozen genetic tests in categories ranging from health to entertainment.

Bay Area-based Helix is a spinout of Illumina, a biotech company that develops DNA sequencing machines. Helix's mission is to make genomics relevant to millions more people than have used services like 23andMe, or have taken genetic tests for medical reasons.

It is hoping to reach that broader audience by partnering with a variety of brands that use genetic data in their marketing campaigns.

Examples of apps on Helix's e-commerce store include EverlyWell's "Breast Milk DHA+", which offers new moms the opportunity to find out about the DHA in their breast milk, and Dot One's "personalized scarf," which puts the pattern of a user's genetic code into a scarf. The company also offers health applications, like an inherited diabetes and cholesterol test, and its other categories are fitness, entertainment, nutrition, and ancestry.

The goal for Helix is to reach a new user-base who might not be aware of genetics or are fearful of the consequences of sharing their sensitive health data with companies (there are some gaps in the laws that protect people from discrimination based on their genetics). To convince these people, Thurston said, "utility must surpass fear." In other words, these tests need to be useful or entertaining enough to convince users to give Helix a shot.

Helix is positioning itself as an "app store," because takes on the task of sequencing a users' DNA in its San Diego lab then curates the apps that can take advantage of that information. Helix provides exome sequencing, which is more extensive than "genotyping" services offered by 23andMe, Ancestry.com and the like.

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Start-up Helix wants you to care about your DNA -- and it's enlisting help from marketers - CNBC

SmartNews Keeping you current The York Gospels (York Minster)

smithsonian.com July 31, 2017

In 2010, bioarchaeologist Matthew Collins of the University of Copenhagen and his colleagues realized that the parchment used in medieval manuscripts, which is made of scraped and stretched animal skins, was actually a repository of information about the history of domestic animals in Europe.

ChrisBaraniukatNew Scientistreports that Collins and histeam have since begun collecting the dry eraser waste of skinsleft when conservators gently cleaned the manuscripts. Using these scraps,they've been able to draw out the DNA and proteins of the animal that sourced the parchment as well as that of any bookworms and humansthat hadcome in contact with the page since.

At a recent symposium on bioarchaeology at Oxfords Bodleian Library, the researchers presentedan unpublished paperwhere they applied DNA techniques as well as traditional techniques to the 1,000-year-old York Gospels, an Anglo-Saxon manuscript, which is one of the few manuscripts to survive the Norman Conquest and the Protestant Reformation.

Ann Gibbons at Science reports that analysis of the parchment led to several surprises. For instance, the 167 folio pages of the York Gospels were made mainly from female calves, which is unusual since its believed they would normally be allowed to grow up and reproduce. But documents report that a cattle disease struck the region around the time the manuscript was produced, meaning there may have been many stillborn or sick calves around to provide the material.

Gibbons also reports that 20 percent of the DNA extracted from theYork Gospelswas human most of it from the bacteria that lived on the skin and noses of priests who took an oath by kissing certain pages. That and other bacteria could give some insight into the health of people in Middle Ages York.

A similar analysis of a Gospel of Luke manuscript by Collins and his colleagues revealedthe book was made from the skins of eight-and-a-half calves, ten-and-a-half sheep, and half a goat, as well as a cover from roe deer and a strap from fallow or red deer. Such mixed parchment suggests that scribes had to carefully manage their resources since their favored skin was not always available.

There are so many possibilities raised by the developing techniques thatGibbons reports researchers dont even know what questions to ask.Bookworm DNA could help determine what region a book was produced or traveled to; parchment DNA could help trace the changes in livestock types and breeds over time; its even possible to find the DNA of specific historical individuals who handled a book during their lifetime.

While scholars have long mined medieval manuscripts to learn about the development of language and writing styles from the texts and gleaninformation about daily life from the illustrations (and paw prints), this new lens into the manuscripts offers a whole new way to mine information frommanuscripts and bringlost chapters ofhistory to life.

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Jason Daley is a Madison, Wisconsin-based writer specializing in natural history, science, travel, and the environment. His work has appeared in Discover, Popular Science, Outside, Mens Journal, and other magazines.

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Medieval Manuscripts Are a DNA Smorgasbord - Smithsonian