Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences
Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences
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DOI：
10.1093/emboj/20.17.4704
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发表时间：
2001-09-03
期刊：
影响因子：
11.4
通讯作者：
Ashworth, A
中科院分区：
文献类型：
--
作者：
Tutt, A;Bertwistle, D;Ashworth, A
BRCA2突变导致家族性早发性乳腺癌和卵巢癌。BRCA2已被认为对维持基因组完整性很重要，并在同源定向双链断裂（DSB）修复的DNA修复中发挥作用。通过研究特定诱导染色体DSB的修复，我们发现Brca2的缺失导致同源定向单链退火导致易出错修复的大幅增加，保守基因转换导致DSB修复的减少。这些数据表明，Brca2的缺失通过刺激使用易出错的同源重组途径，导致重复序列之间发生的染色体dsb的错误修复。此外，Brca2的缺失导致自发DNA损伤和丝裂霉素c诱导的DNA交联的全基因组易发错误修复的大量增加，代价是姐妹染色单体重组的无错误修复。这为在缺乏BRCA2的肿瘤细胞中诱导基因组不稳定的机制提供了见解。
Mutation of BRCA2 causes familial early onset breast and ovarian cancer. BRCA2 has been suggested to be important for the maintenance of genome integrity and to have a role in DNA repair by homology-directed double-strand break (DSB) repair. By studying the repair of a specific induced chromosomal DSB we show that loss of Brca2 leads to a substantial increase in error-prone repair by homology-directed single-strand annealing and a reduction in DSB repair by conservative gene conversion. These data demonstrate that loss of Brca2 causes misrepair of chromosomal DSBs occurring between repeated sequences by stimulating use of an error-prone homologous recombination pathway. Furthermore, loss of Brca2 causes a large increase in genome-wide error-prone repair of both spontaneous DNA damage and mitomycin C-induced DNA cross-links at the expense of error-free repair by sister chromatid recombination. This provides insight into the mechanisms that induce genome instability in tumour cells lacking BRCA2.