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BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.

Nature (2017-10-05)
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, Patrick Sung
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.

MATERIALS
Product Number
Brand
Product Description

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MISSION® esiRNA, targeting human BRCA2
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Magnesium methyl carbonate solution, 2.0 M in DMF
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Monoclonal ANTI-FLAG® M2-Peroxidase (HRP) antibody produced in mouse, clone M2, purified immunoglobulin, buffered aqueous glycerol solution