Abstract
Activation-induced cytidine deaminase (AID) is required for somatic hypermutation and immunoglobulin class switching in activated B cells. Because AID has no known target-site specificity, there have been efforts to identify non-immunoglobulin AID targets. We show here that AID acts promiscuously, generating widespread DNA double-strand breaks (DSBs), genomic instability and cytotoxicity in B cells with less homologous recombination ability. We demonstrate that the homologous-recombination factor XRCC2 suppressed AID-induced off-target DSBs, promoting B cell survival. Finally, we suggest that aberrations that affect human chromosome 7q36, including XRCC2, correlate with genomic instability in B cell cancers. Our findings demonstrate that AID has promiscuous genomic DSB-inducing activity, identify homologous recombination as a safeguard against off-target AID action, and have implications for genomic instability in B cell cancers.
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Acknowledgements
We thank T. Honjo (Kyoto Univesity), R. Maser and S. LaSalle (The Jackson Laboratory) and A.Y. Tsygankov (Temple University School of Medicine) for reagents and mice; C. Boboila, B. Schwer and F.W. Alt (Children's Hospital, Boston) and J. Chaudhuri (Memorial Sloan-Kettering Cancer Center) for reagents and technical assistance; and the Jackson Laboratory Gene Expression, Molecular Biology and Flow Cytometry Services for technical support. Supported by the US National Institutes of Health (R01CA138646, P20RR018789-06, T32DK07449-26 and P30CA034196) and the Maine Cancer Foundation.
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M.G.H. designed and did experiments and wrote the manuscript; J.A., E.C., N.M.D., J.M. and K.J.S. did experiments and contributed data; Y.H., B.L.K. and R.Y.W. contributed data; and K.D.M. designed experiments and wrote the manuscript.
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Hasham, M., Donghia, N., Coffey, E. et al. Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination. Nat Immunol 11, 820–826 (2010). https://doi.org/10.1038/ni.1909
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DOI: https://doi.org/10.1038/ni.1909
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