title: Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination.
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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Muneer G
authors.initials: MG
authors.lastname: Hasham
authors.forename: Nina M
authors.initials: NM
authors.lastname: Donghia
authors.forename: Eliot
authors.initials: E
authors.lastname: Coffey
authors.forename: Jane
authors.initials: J
authors.lastname: Maynard
authors.forename: Kathy J
authors.initials: KJ
authors.lastname: Snow
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Ames
authors.forename: Robert Y
authors.initials: RY
authors.lastname: Wilpan
authors.forename: Yishu
authors.initials: Y
authors.lastname: He
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: King
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Mills
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology; D002453:Cell Cycle; D002470:Cell Survival; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000378:metabolism*; D053960:DNA Breaks; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D042822:Genomic Instability; D006801:Humans; D011995:Recombination, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; C113187:XRCC2 protein, human; D003564:Cytidine Deaminase