3 years ago

BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing

BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing
Lucy Lu, Fengshan Liang, Timsi Rao, Weixing Zhao, Gary M. Kupfer, Ryan B. Jensen, David G. Maranon, Patrick Sung, Xiaoyong Chen, Eric C. Greene, Claudia Wiese, Judit Jimenez-Sainz, Chen Sheng, Yanhong Deng, Weibin Wang, Yong Xiong, Justin B. Steinfeld, Youngho Kwon, Xuemei Song, Chu Jian Ma
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.

Publisher URL: http://dx.doi.org/10.1038/nature24060

DOI: 10.1038/nature24060

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