BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing

Weixing Zhao (), Justin B. Steinfeld, Fengshan Liang, Xiaoyong Chen, David G. Maranon, Chu Jian Ma, Youngho Kwon, Timsi Rao, Weibin Wang, Chen Sheng, Xuemei Song, Yanhong Deng, Judit Jimenez-Sainz, Lucy Lu, Ryan B. Jensen, Yong Xiong, Gary M. Kupfer, Claudia Wiese, Eric C. Greene () and Patrick Sung ()
Additional contact information
Weixing Zhao: Yale University School of Medicine
Justin B. Steinfeld: Columbia University
Fengshan Liang: Yale University School of Medicine
Xiaoyong Chen: Section of Hematology-Oncology, Yale University School of Medicine
David G. Maranon: Colorado State University
Chu Jian Ma: Columbia University
Youngho Kwon: Yale University School of Medicine
Timsi Rao: Yale University School of Medicine
Weibin Wang: Yale University School of Medicine
Chen Sheng: Yale University School of Medicine
Xuemei Song: Yale Center for Analytical Sciences, Yale School of Public Health
Yanhong Deng: Yale Center for Analytical Sciences, Yale School of Public Health
Judit Jimenez-Sainz: Yale University School of Medicine
Lucy Lu: Yale University School of Medicine
Ryan B. Jensen: Yale University School of Medicine
Yong Xiong: Yale University School of Medicine
Gary M. Kupfer: Section of Hematology-Oncology, Yale University School of Medicine
Claudia Wiese: Colorado State University
Eric C. Greene: Columbia University
Patrick Sung: Yale University School of Medicine

Nature, 2017, vol. 550, issue 7676, 360-365

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/nature24060

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