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Locking mechanism found for 'scissors' that cut DNA

Posted: December 25, 2014 at 4:43 am

Fast Facts:

-So that the immune system can adapt to fight a wide range of foes, the enzyme RAG clips DNA to create segments that are then mixed and matched to produce billions of specialized foe-finding proteins.

-New findings show that RAG contains a safety lock that prevents helter-skelter clipping.

-A mutation that jams the lock can be overridden by another mutation that removes the locking mechanism.

Researchers at Johns Hopkins have discovered what keeps an enzyme from becoming overzealous in its clipping of DNA. Since controlled clipping is required for the production of specialized immune system proteins, an understanding of what keeps the enzyme in check should help explain why its mutant forms can lead to immunodeficiency and cancer. A summary of the results will be published online in the journal Cell Reports on Dec. 24.

The immune system relies on the formation of specialized proteins (antibodies) that can recognize and immobilize foreign invaders like viruses and bacteria. Since storing individual blueprints for each of these proteins would require huge amounts of DNA, the body instead mixes and matches different chunks of sequence to produce roughly 300 trillion possibilities. This mixing and matching, called recombination, requires that DNA be clipped by the enzyme RAG.

"Recombination is essential for the immune system's ability to recognize and fight new enemies, but too much clipping can cause harmful chromosome rearrangements," says Stephen Desiderio, M.D., Ph.D., director of the Institute for Basic Biomedical Sciences and the senior researcher for the study. "We now know that RAG has a built-in lock that prevents it from getting out of hand as it clips DNA."

To keep the system efficient, each immune cell makes only a single antibody and only does so after being activated. Several years ago, Desiderio's group found that this level of control is enforced by a segment of RAG called the PHD. The PHD binds to a chemical tag called H3K4me3, which is only found on DNA that is actively being rewritten as RNA. This prevents RAG from recombining DNA that is not active.

When the PHD segment was mutated and nonfunctional, RAG couldn't cut, suggesting that the binding of the PHD to H3K4me3 was required for RAG's function. But when the PHD was deleted entirely, RAG was just fine. To understand what was happening, Desiderio's team looked for mutations that would bring function back to the mutant PHD. They found that when 13 amino acids were deleted in front of the mutant PHD segment, RAG cut even better than it normally does.

Alyssa Ward, a graduate student in Desiderio's laboratory, says that the system works like the bolt on a door. The PHD piece is the lock, H3K4me3 is the key and the deleted piece is the actual bolt. When all of the pieces are normal, H3K4me3 unlocks the PHD segment, which moves the bolt so that the door can open-- i.e., so that RAG can cut. If there is a mutation in the PHD, the key won't fit the lock, so the door remains bolted. But, if the lock or bolt is removed entirely, the door can open and close freely.

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Locking mechanism found for 'scissors' that cut DNA

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December 22nd – Dean Burnett – Cosmic Genome Science Advent Calendar – Video

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December 22nd - Dean Burnett - Cosmic Genome Science Advent Calendar
Dr Dean Burnett is interested in a world where we can replace old people #39;s blood... Every day a new free science clip from the good people at Cosmic Genome. Head to cosmicgenome.com/advent...

By: The Incomplete Map of the Cosmic Genome

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December 22nd - Dean Burnett - Cosmic Genome Science Advent Calendar - Video

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December 21st – Dr Ben Goldacre – Cosmic Genome Science Advent Calendar – Video

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December 21st - Dr Ben Goldacre - Cosmic Genome Science Advent Calendar
From a successful year for the All Trials campaign, to new book #39;I Think You #39;ll Find It #39;s a Bit More Complicated Than That #39;, here #39;s 2014 with Dr Ben Goldacre. Every day a new free science...

By: The Incomplete Map of the Cosmic Genome

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December 21st - Dr Ben Goldacre - Cosmic Genome Science Advent Calendar - Video

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December 23rd – Helen Czerski – Cosmic Genome Science Advent Calendar – Video

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December 23rd - Helen Czerski - Cosmic Genome Science Advent Calendar
Dr Helen Czerski is excited about the mapping of the Earth #39;s carbon dioxide. Every day a new free science clip from the good people at Cosmic Genome. Head to cosmicgenome.com/advent Subscribe.

By: The Incomplete Map of the Cosmic Genome

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December 23rd - Helen Czerski - Cosmic Genome Science Advent Calendar - Video

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Channel Revitol Eczema Cream – Video

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ezcema – Video

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By: Fazeski Sekilo

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Scalp Eczema – Revitol Eczema Cream – Video

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http://www.try-revitoleczemacream.com/ Scalp Eczema Eczema is usually a recurring skin affliction and you should never know whether you #39;ve got gotten rid of it or you cannot. It might recur...

By: Sarah Jacobs

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Whole-genome sequencing can identify cancer-linked mutations

Posted: at 4:42 am

WASHINGTON: Scientists have found that whole-genome sequencing can be used to identify patients' risk for hereditary cancer.

In a first of its kind study, researchers at University of Texas Southwestern Medical Center used whole-genome sequencing to evaluate a series of 258 cancer patients' genomes to improve the ability to diagnose cancer-predisposing mutations.

"Whole-genome sequencing is a new genetic tool that can determine more of a person's DNA sequence than ever before," said Dr Theodora Ross, Professor of Internal Medicine and Director of UT Southwestern's Cancer Genetics Programme.

"Our results show that nearly 90 per cent of clinically identified mutations were confidently detected and additional cancer gene mutations were discovered, which together with the decreasing costs associated with whole-genome sequencing means that this method will improve patient care, as well as lead to discovery of new cancer genes," Ross said.

About 5 to 10 per cent of all cancers are caused by known inherited gene mutations. These mutations are passed down from generation to generation.

Mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer. BRCA gene mutations are best known for their breast cancer risk, but they also cause increased risk for ovarian, prostate, pancreatic, and other cancers.

In addition, there are many different genes, including ATM, CDH1, CHEK2, PALB2, PTEN, and TP53, that are associated with an increased risk for breast cancer, and researchers are continually discovering additional genes that may affect cancer predisposition.

In the study, researchers developed new methods to analyse the large amount of data generated by whole-genome sequencing.

Ross' team devised a method to compare the group of patients with BRCA1 or BRCA2 mutations to a group of patients without BRCA mutations.

All expected BRCA1 and BRCA2 mutations were detected in the BRCA group, with at least 88.6 per cent of mutations confidently detected. In contrast, different cancer gene mutations were found in the cohort without BRCA mutations.

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Horrible Bosses star standing tall in Hollywood

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At a time when more Hollywood comedians are flaunting their loudness and lewdness, Jason Sudeikis' rise to stardom seems remarkably understated and subdued.

Sure, there have been public romances with leading actresses (Sudeikis previously dated Mad Men's January Jones and he is now happily ensconced with Olivia Wilde and their 7-month-old son Otis).

But, unlike many of his peers, Sudeikis hasn't had to apologise for politically incorrect rants that went viral, or launched a war on Twitter.

He is never asked about any similarities between himself and the screwed-up characters he plays on screen - whether it's a family man going off the rails in Hall Pass or a small-time drug dealer in We're the Millers - for good reason.

Sudeikis, 39, is now one of the hottest properties in Hollywood, having featured in four films that have grossed more than US$200 million ($258 million) worldwide in the past six years.

He possesses a boyish, goofy comedic appeal, his relaxed mien enhanced by the fact that he's a late developer by Hollywood standards - he only acted in his first film in 2007.

Sudeikis' new film, Horrible Bosses 2, is hardly understated or subdued. Horrible Bosses was a 2011 black comedy in which a trio of bitter workers played by Sudeikis, Jason Bateman and Charlie Day murdered their tyrannical managers.

Most of the starry supporting players return for the sequel - Jennifer Aniston as a sex-crazed dentist, Kevin Spacey as a psychopathic CEO and Jamie Foxx as the ex-con "murder consultant".

Oscar-winner Christoph Waltz is a millionaire investor who steals the workers' money.

The success of Horrible Bosses took Hollywood off-guard, tapping into audiences' own experiences with micro-managing superiors in the workplace.

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Horrible Bosses star standing tall in Hollywood

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A White Christmas

Posted: at 4:42 am

I recently heard that White Christmas is now politically incorrect.

Bing rolls over in his grave. How foolish.

White Christmas is not about skin color, but about snow, which is white. I am praying for each of you who read this, a white Christmas, even if it doesnt snow on this or any Christmas. Here is what I mean.

If you come to church at Immanuel at Christmas you will see that the cloths that decorate the altar have turned to white. White is the color of holiness, purity, and the absence of that which makes unclean. That is not a description of us, even at Christmas.

The pressures that surround this season often bring out the worst in people. As someone recently said, We dont have a skin problem. We have a sin problem. White is the color that reflects the perfect, sinless Son of God born into our world of sin, to buy it back with the price of His own suffering and death.

What is most remarkable is that what this Christmas Child would do on the cross makes us white (Dont Think Skin Color!).

Christs suffering, death and resurrection makes us sinless, holy and perfect in the eyes of our God. The Christmas prophet Isaiah wrote: Though your sin (not skin!) is like scarlet, it shall be white as snow. A Norman Rockwell, Bing Crosby, White Christmas would be nice for a moment or two. The White (forgiven, at peace with God and man, declared holy) Christmas that comes from this Child whose birth we celebrate again this year, who was born to die and rise for us, gives to us a White Christmas forever.

No need to dream of a White Christmas. It is Gods gift to you in His Son. I am

Yours in Christ,

Pastor Mark Bangert

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A White Christmas

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