BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.

作者：Zhao, Weixing; Steinfeld, Justin B; Liang, Fengshan; Chen, Xiaoyong; Maranon, David G; Jian Ma, Chu; Kwon, Youngho; Rao, Timsi; Wang, Weibin; Sheng, Chen; Song, Xuemei; Deng, Yanhong; Jimenez-Sainz, Judit; Lu, Lucy; Jensen, Ryan B; Xiong, Yong; Kupfer, Gary M; Wiese, Claudia; Greene, Eric C; Sung, Patrick

来源：Nature, 2017, 550(7676): 360-365.

DOI：10.1038/nature24060

The tumour suppressor complex BRCA1-BARD1 functions in the repair of DNA double-stranded breaks by homologous recombination. During this process, BRCA1-BARD1 facilitates the nucleolytic resection of DNA ends to generate a single-stranded template for the recruitment of another tumour suppressor complex, BRCA2-PALB2, and the recombinase RAD51. Here, by examining purified wild-type and mutant BRCA1-BARD1, we show that both BRCA1 and BARD1 bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. We provide evidence that BRCA1 and BARD1 are indispensable for RAD51 stimulation. Notably, BRCA1-BARD1 mutants with weakened RAD51 interactions show compromised DNA joint formation and impaired mediation of homologous recombination and DNA repair in cells. Our results identify a late role of BRCA1-BARD1 in homologous recombination, an attribute of the tumour suppressor complex that could be targeted in cancer therapy.

• 单位
  new; Yale University School of Medicine; Yale University school of medicine; Yale University, School of Medicine; columbia University