Widespread genomic breaks generated by 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 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.
Hasham
Muneer G
MG
The Jackson Laboratory, Bar Harbor, ME, USA.
Donghia
Nina M
NM
Coffey
Eliot
E
Maynard
Jane
J
Snow
Kathy J
KJ
Ames
Jacquelyn
J
Wilpan
Robert Y
RY
He
Yishu
Y
King
Benjamin L
BL
Mills
Kevin D
KD
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
D004268:DNA-Binding Proteins; C113187:XRCC2 protein, human; D003564:Cytidine Deaminase