Researchers at Johns Hopkins have discovered what keeps an enzyme called RAG (recombination activating gene) from becoming overzealous in its clipping of DNA. Because 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 was published online in an open-access article in Cell Reports on December 24, 2014. The immune system relies on the formation of specialized proteins (antibodies) that can recognize and immobilize foreign invaders like viruses and bacteria. Because 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 RAG enzyme. "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 at Johns Hopkins 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, Dr. Desiderio's group found that this level of control is enforced by a segment of RAG called the PHD segment. The PHD segment 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.
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