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

Activation induced cytidine deaminase (AID) is required for somatic hypermutation and immunoglobulin class switching in activated B cells. Because AID possesses no known target site specificity, there have been efforts to identify non-immunoglobulin AID targets. We show that AID acts promiscuously, generating widespread DNA double strand breaks (DSB), genomic instability and cytotoxicity in B cells with diminished homologous recombination (HR) capability. We demonstrate that the HR factor XRCC2 suppresses AID-induced off-target DSBs, promoting B cell survival. Finally, we suggest that aberrations affecting 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 HR as a safeguard against off-target AID action, and have implications for genomic instability in B cell cancers.