Locking mechanism for DNA-cutting "scissors" discovered

December 27, 2014

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John Hopton for redOrbit.com Your Universe Online

Researchers at Johns Hopkins University have uncovered secrets in the way that DNA operates during the process of fighting problems within the body, and believe that the discovery could have implications for our understanding of immunodeficiencies and cancers.

The scientists claim to have identified a locking mechanism for the scissors that cut DNA and allow it to mix and match in order to produce combinations which fight threats to the body, such as viruses and bacteria. The enzyme RAG clips DNA so that different chunks of sequence can be combined to produce roughly 300 trillion possibilities of specialized immune system proteins, also known as antibodies, in a process known as recombination. The system breaks down when over-clipping occurs, but now the researchers believe they understand the locking system that helps to prevent over-clipping.

Recombination is essential for the immune systems 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.

Tests on mice now aim to examine what goes wrong in those immunodeficiencies and cancers linked to mutations in RAG. The first thought that often occurs when hearing such stories, along with thats not very fair on those mice, but its for a good cause so what the hell, is wow, what incredible work, please can you hurry it along? Such a fundamental discovery gives renewed hope that one day afflictions such as cancer can be fully understood, and then fully prevented or treated. Yet at the same time, the complexities of what needs to be achieved are discouragingly brought home, even if they do make you marvel at the wonder of the discoveries made so far.

How does the cutting and locking system work? To ensure maximum efficiency within the process, each immune cell makes only a single antibody and only does so after it is activated. Desiderio and his team had previously found that this regulation is controlled 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, the vehicle for carrying instructions from DNA that control the synthesis of proteins. The process prevents RAG from recombining DNA that is not active.

When the PHD segment was mutated and nonfunctional, explains the Johns Hopkins report, RAG couldnt cut, suggesting that the binding of the PHD to H3K4me3 was required for RAGs function. But when the PHD was deleted entirely, RAG was just fine.

Desiderios 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, RAGs cutting had greater efficiency.

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Locking mechanism for DNA-cutting "scissors" discovered