Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination
Widespread genomic breaks generated by activation-induced cytidine deaminase are prevented by homologous recombination
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DOI：
10.1038/ni.1909
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发表时间：
2010-09-01
影响因子：
30.5
通讯作者：
Mills, Kevin D.
中科院分区：
文献类型：
--
作者：
Hasham, Muneer G.;Donghia, Nina M.;Mills, Kevin D.
活化诱导的胞苷脱氨酶（AID）是活化B细胞中体细胞超突变和免疫球蛋白类别转换所必需的。由于AID没有已知的靶位点特异性，因此一直在努力鉴定非免疫球蛋白AID靶点。我们在这里表明，艾滋病行为混杂，产生广泛的DNA双链断裂（DSB），基因组不稳定性和细胞毒性的B细胞同源重组能力较低。我们证明同源重组因子XRCC 2抑制了艾滋病诱导的脱靶DSB，促进了B细胞的存活。最后，我们认为影响人类染色体7q36的畸变，包括XRCC 2，与B细胞癌中的基因组不稳定性相关。我们的研究结果表明，AID具有混杂的基因组DSB诱导活性，确定同源重组作为对脱靶AID作用的保障，并对B细胞癌症中的基因组不稳定性有影响。
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.