Researchers discovered the mechanism that keeps enzymes from "overclipping" DNA strands.
The findings could help explain why the enzyme's "mutant form" can lead to immunodeficiency and cancer, Johns Hopkins Medicine reported.
The immune system uses antibodies to identify and fight foreign invaders such as viruses, but storing enough data to pinpoint each of these proteins would require a huge amount of DNA. In order to get around this the body "mixes and matches" different sequences in a process called "recombination," which requires the DNA to 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," said Stephen Desiderio, 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."
Each immune cell produces a single type of antibody after being activated, the control of this process enforced by a segment of RAG dubbed PHD. This segment binds to the chemical tag H3K4me3, which is only found on DNA that is actively being rewritten as RNA. The process prevents RAG from recombining DNA that is inactive.
Researchers found when the PHD segment mutated to become nonfunctional, RAG could no longer snip the DNA, which suggests the binding of the PHD to H3K4me3 is essential in the process. In their study the research team was able to identified 13 amino acids that when deleted from the mutant PHD segment allowed RAG to cut even more efficiently than it normally does.
"It was previously thought that H3K4me3 was simply a docking site for proteins," Desiderio said. "This study shows that it is also a key that activates them."
The findings were published in a recent edition of the journal Cell Reports.
