Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination

MG Hasham, NM Donghia, E Coffey, J Maynard… - Nature …, 2010 - nature.com
MG Hasham, NM Donghia, E Coffey, J Maynard, KJ Snow, J Ames, RY Wilpan, Y He…
Nature immunology, 2010nature.com
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 …
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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