Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.
Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.
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DOI：
10.1084/jem.20020851
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发表时间：
2002-08-19
期刊：
影响因子：
--
通讯作者：
Nussenzweig A
中科院分区：
文献类型：
--
作者：
Difilippantonio MJ;Petersen S;Chen HT;Johnson R;Jasin M;Kanaar R;Ried T;Nussenzweig A
非相互易位和基因扩增在人类肿瘤中常见。虽然对导致这种畸变的机制知之甚少，但组织培养模型预测它们可能源于DNA断裂，随后是染色单体融合、不对称有丝分裂断裂和复制的循环。在非同源末端连接（NHEJ）DNA修复蛋白和p53肿瘤抑制基因缺陷的小鼠发展淋巴瘤在早期的年龄窝藏扩增的IgH/c-myc融合。在这里，我们报告说，这些染色体重排是由重组激活基因（RAG）诱导的DNA裂解。随后的DNA修复事件并列IgH和c-myc介导的断裂诱导的复制途径。断裂-融合-桥的循环导致IgH/c-myc的扩增，而染色体稳定通过端粒捕获发生。因此，NHEJ缺陷的小鼠提供了极好的模型来研究肿瘤发生期间不平衡易位和扩增事件的病因。
Nonreciprocal translocations and gene amplifications are commonly found in human tumors. Although little is known about the mechanisms leading to such aberrations, tissue culture models predict that they can arise from DNA breakage, followed by cycles of chromatid fusion, asymmetric mitotic breakage, and replication. Mice deficient in both a nonhomologous end joining (NHEJ) DNA repair protein and the p53 tumor suppressor develop lymphomas at an early age harboring amplification of an IgH/c-myc fusion. Here we report that these chromosomal rearrangements are initiated by a recombination activating gene (RAG)-induced DNA cleavage. Subsequent DNA repair events juxtaposing IgH and c-myc are mediated by a break-induced replication pathway. Cycles of breakage-fusion-bridge result in amplification of IgH/c-myc while chromosome stabilization occurs through telomere capture. Thus, mice deficient in NHEJ provide excellent models to study the etiology of unbalanced translocations and amplification events during tumorigenesis.
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