02:15pm Thursday 21 September 2017

Jackson Laboratory researchers gain new insight into DNA break and repair mechanisms

In a paper published in Nature Immunology, Assistant Professor Kevin Mills, Ph.D., and Postdoctoral Associate Muneer Hasham, Ph.D., demonstrate a vital balance between a DNA-repair protein called XRCC2 and a DNA-breaking enzyme known as activation-induced cytidine deaminase (AICDA) in immune system cells called B cells.

The human body is constantly barraged by the outside world. Foreign substances, particles and microorganisms, collectively known as antigens, try to enter. And while the immune system mounts a protective response, there’s a basic problem. Each person’s immune system must respond to tens of millions of distinct and different antigens, armed with only about 20,000 genes.

The solution? The immune system uses the same stretch of DNA to make large numbers of different antibodies by patching together different segments in different ways. Think of the word “Saskatchewan.” By extracting different letters, you can make a number of different words: skate, chew, sat, hen and so on. In the same way, the immune system is able reshuffle segments of DNA to respond to a huge number of antigens, and to fine-tune the immune response to individual antigens.

These are elegant systems, but they require that the DNA be broken and patched back together often, and with high precision. XRCC2 is a key player in high fidelity repair in non-immune cells. Mills and his team have now found that XRCC2 is needed to protect the genome of B cells. Its absence leads to a high frequency of DNA breaks, which in turn can cause cells to die or become critically unstable.

AICDA breaks the DNA and XRCC2 repairs it. But in the Nature Immunology paper, Mills and Hasham show there is an unexpected twist to the story.

“You’d expect AICDA to have high target specificity, with its activity precisely confined to certain regions in the genes responsible for antibody production,” says Mills. “But the DNA damage is really more like a shotgun blast. AICDA creates a lot of DNA breaks at many locations in the genome, and the high fidelity repair function of XRCC2 is then essential for repairing off-target breaks.”

The reasons behind such a seemingly high-risk system are unclear, but the consequences when it doesn’t function perfectly may be obvious. In addition to possible immunodeficiency problems, too much damage might lead to cancers such as lymphoma and leukemia.

“XRCC2 may be compromised in a broad range of cancers,” says Mills. And that could be more important than previously appreciated. “Our work shows that even a partial reduction of XRCC2 function can lead to most, maybe all, of the effects we have seen when it is completely absent.”

Hasham, who established the research system that allowed the team to perform the necessary experiments, adds, “Kevin had the insight that investigating the actions of the damaging agent, AID, would help us understand more about the repair system’s function. AICDA creates off-target damage, collateral damage, in the DNA far more often than anyone suspected.”

There are many questions remaining to be investigated, but the findings have important potential implications. In particular, there may be ways to provoke increased DNA damage in cancer cells that lead to catastrophic failure and cell death. By giving the dysfunctional balance between damage and repair an added push in malignant cells, it might be possible to eliminate those cells with little effect on healthy cells and tissue.

The Jackson Laboratory is an independent, nonprofit biomedical research institution based in Bar Harbor, Maine, with a facility in Sacramento, Calif. Its mission is to discover the genetic basis for preventing, treating and curing human diseases, and to enable research and education for the global biomedical community.

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Hasham et al.: Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination. Nature Immunology, Advance Online Publication, doi 10.1038/ni.1909.

Contact(s): Joyce Peterson, 207-288-6058

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