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

• Published in: Nature immunology Vol. 11; no. 9; pp. 820 - 826
• Main Authors: Donghia, Nina M, Coffey, Eliot, He, Yishu, Wilpan, Robert Y, Ames, Jacquelyn, Mills, Kevin D, Maynard, Jane, King, Benjamin L, Hasham, Muneer G, Snow, Kathy J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-09-2010; Nature Publishing Group
• Subjects: 631/208/737/211; 631/250/1619/40; 631/337/1427/2190; 631/45/607; B cells; B-Lymphocytes - immunology; Biomedical and Life Sciences; Biomedicine; Cell Cycle; Cell Survival; Cells, Cultured; Cytidine Deaminase - metabolism; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA Breaks; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Flow Cytometry; Genetic aspects; Genetic recombination; Genomic Instability; Genomics; Humans; Immunoglobulins; Immunology; Infectious Diseases; Physiological aspects; Recombination, Genetic - genetics; Reverse Transcriptase Polymerase Chain Reaction; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.1909

Activation-induced cytidine deaminase triggers somatic hypermutation and immunoglobulin class switching. Mills and colleagues show that it can also cause widespread mutations outside the immunoglobulin heavy-chain locus.
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.