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

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Cell-Cycle, Cell-Survival, Cells-Cultured, Cytidine-Deaminase, DNA-Breaks, DNA-Binding-Proteins, Flow-Cytometry, Genomic-Instability, Humans, Recombination-Genetic, Reverse-Transcriptase-Polymerase-Chain-Reaction

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Nat Immunol 2010 Sep; 11(9):820-6.


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.