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首页> 外文期刊>Molecular and Cellular Biology >Rapid Recruitment of BRCA1 to DNA Double-Strand Breaks Is Dependent on Its Association with Ku80
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Rapid Recruitment of BRCA1 to DNA Double-Strand Breaks Is Dependent on Its Association with Ku80

机译：将BRCA1快速招募至DNA双链断裂取决于其与Ku80的关联

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BRCA1 is the first susceptibility gene to be linked to breast and ovarian cancers. Although mounting evidence has indicated that BRCA1 participates in DNA double-strand break (DSB) repair pathways, its precise mechanism is still unclear. Here, we analyzed the in situ response of BRCA1 at DSBs produced by laser microirradiation. The amino (N)- and carboxyl (C)-terminal fragments of BRCA1 accumulated independently at DSBs with distinct kinetics. The N-terminal BRCA1 fragment accumulated immediately after laser irradiation at DSBs and dissociated rapidly. In contrast, the C-terminal fragment of BRCA1 accumulated more slowly at DSBs but remained at the sites. Interestingly, rapid accumulation of the BRCA1 N terminus, but not the C terminus, at DSBs depended on Ku80, which functions in the nonhomologous end-joining (NHEJ) pathway, independently of BARD1, which binds to the N terminus of BRCA1. Two small regions in the N terminus of BRCA1 independently accumulated at DSBs and interacted with Ku80. Missense mutations found within the N terminus of BRCA1 in cancers significantly changed the kinetics of its accumulation at DSBs. A P142H mutant failed to associate with Ku80 and restore resistance to irradiation in BRCA1-deficient cells. These might provide a molecular basis of the involvement of BRCA1 in the NHEJ pathway of the DSB repair process.
机译： BRCA1 是第一个与乳腺癌和卵巢癌相关的易感基因。尽管越来越多的证据表明BRCA1参与DNA双链断裂（DSB）修复途径，但其确切机制仍不清楚。在这里，我们分析了BRCA1在激光微辐照产生的DSB上的原位响应。 BRCA1的氨基（N）和羧基（C）末端片段在DSB处以不同的动力学独立积累。 N端BRCA1片段在DSB激光照射后立即聚集并迅速解离。相反，BRCA1的C端片段在DSB处积累较慢，但仍保留在位点处。有趣的是，BRCA1 N末端而不是C末端在DSB处的快速积累取决于Ku80，其在非同源末端连接（NHEJ）途径中起作用，独立于与BRCA1的N末端结合的BARD1。 BRCA1 N末端的两个小区域独立积累在DSB处，并与Ku80相互作用。在癌症的BRCA1 N端发现的错义突变显着改变了其在DSB处积累的动力学。一个P142H突变体未能与Ku80关联，并恢复 BRCA1 缺陷细胞对辐射的抗性。这些可能提供BRCA1参与DSB修复过程的NHEJ途径的分子基础。

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