BRCA2 is epistatic to the RAD51 paralogs in response to DNA damage.
BRCA2 is epistatic to the RAD51 paralogs in response to DNA damage.
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DOI：
10.1016/j.dnarep.2012.12.007
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发表时间：
2013-04-01
期刊：
影响因子：
3.8
通讯作者：
Kowalczykowski, Stephen C.
中科院分区：
文献类型：
--
作者：
Jensen, Ryan B.;Ozes, Ali;Kim, Taeho;Estep, Allison;Kowalczykowski, Stephen C.
同源重组在DNA双链断裂的高保真修复中起着重要作用。在这个过程中的一个核心球员，RAD 51，聚合到单链DNA和搜索同源性的双链供体DNA分子，通常是姐妹染色单体。同源重组是哺乳动物细胞中高度调节的事件：一些蛋白质具有直接的酶功能，其他蛋白质介导或克服该过程中的限速步骤，还有一些蛋白质发出细胞周期停滞信号以允许修复发生。虽然人BRCA2蛋白在递送和装载RAD 51到切除DNA断裂后产生的单链DNA上具有明确的作用，但RAD 51旁系同源物的机制功能仍不清楚。在这项研究中，我们试图确定在DNA DSB修复过程中BRCA 2和RAD 51旁系同源物之间的遗传相互作用。我们利用siRNA介导的敲除人类细胞中的这些蛋白质来评估它们对DNA损伤反应的影响。结果表明，BRCA2单独的损失比任何单个RAD 51旁系同源物的损失赋予更严重的表型，并且BRCA2对所测试的四种旁系同源物中的每一种都是上位性的。
Homologous recombination plays an important role in the high-fidelity repair of DNA double-strand breaks. A central player in this process, RAD51, polymerizes onto single-stranded DNA and searches for homology in a duplex donor DNA molecule, usually the sister chromatid. Homologous recombination is a highly regulated event in mammalian cells: some proteins have direct enzymatic functions, others mediate or overcome rate-limiting steps in the process, and still others signal cell cycle arrest to allow repair to occur. While the human BRCA2 protein has a clear role in delivering and loading RAD51 onto single-stranded DNA generated after resection of the DNA break, the mechanistic functions of the RAD51 paralogs remain unclear. In this study, we sought to determine the genetic interactions between BRCA2 and the RAD51 paralogs during DNA DSB repair. We utilized siRNA-mediated knockdown of these proteins in human cells to assess their impact on the DNA damage response. The results indicate that loss of BRCA2 alone imparts a more severe phenotype than the loss of any individual RAD51 paralog and that BRCA2 is epistatic to each of the four paralogs tested.
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