Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair
Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair
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DOI：
10.1074/jbc.m710245200
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发表时间：
2008-03-21
影响因子：
4.8
通讯作者：
Wu, Xiaohua
中科院分区：
文献类型：
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作者：
Chen, Longchuan;Nievera, Christian J.;Wu, Xiaohua
BRCA 1在同源重组介导的DNA双链断裂修复中起重要作用，但其具体机制尚不清楚。在这里，我们描述了BRCA 1形成一个复杂的CtIP和MRN（Mre 11/Rad 50/Nbs 1）在细胞周期依赖性的方式。值得注意的是，复合物的形成，特别是电离辐射增强的BRCA 1与MRN的关联，需要细胞周期蛋白依赖性激酶活性。CtIP直接与Nbs 1相互作用。BRCA 1与MRN的体内结合在很大程度上依赖于CtIP与BRCA 1 C末端BRCT结构域的结合，而BRCA 1 N末端也有助于其与MRN的结合。CtIP以及BRCA 1与CtIP和MRN的相互作用对于IR诱导的单链DNA形成和细胞对辐射的抗性至关重要。因此，CtIP本身是有效的HR介导的DSB修复所必需的，如BRCA 1和MRN。这些研究表明，BRCA1.CtIP.MRN的复合物形成对于促进DSB切除以产生HR介导的DSB修复所需的单链DNA是重要的。由于细胞周期蛋白依赖性激酶对于建立IR增强的MRN与BRCA 1的相互作用是重要的，我们认为BRCA 1、CtIP和MRN的细胞周期依赖性复合物形成有助于激活细胞周期S期和G（2）期HR介导的DSB修复。
BRCA1 plays an important role in the homologous recombination (HR)-mediated DNA double-strand break (DSB) repair, but the mechanism is not clear. Here we describe that BRCA1 forms a complex with CtIP and MRN (Mre11/Rad50/Nbs1) in a cell cycle-dependent manner. Significantly, the complex formation, especially the ionizing radiation-enhanced association of BRCA1 with MRN, requires cyclin-dependent kinase activity. CtIP directly interacts with Nbs1. The in vivo association of BRCA1 with MRN is largely dependent on the association of CtIP with the BRCT domains at the C terminus of BRCA1, whereas the N terminus of BRCA1 also contributes to its association with MRN. CtIP, as well as the interaction of BRCA1 with CtIP and MRN, is critical for IR-induced single-stranded DNA formation and cellular resistance to radiation. Consistently, CtIP itself is required for efficient HR-mediated DSB repair, like BRCA1 and MRN. These studies suggest that the complex formation of BRCA1.CtIP.MRN is important for facilitating DSB resection to generate single-stranded DNA that is needed for HR-mediated DSB repair. Because cyclin-dependent kinase is important for establishing IR-enhanced interaction of MRN with BRCA1, we propose that the cell cycle-dependent complex formation of BRCA1, CtIP, and MRN contributes to the activation of HR-mediated DSB repair in the S and G(2) phases of the cell cycle.