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, Patrick Sung

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

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.

Original languageEnglish (US)
Article numbernature24060
JournalNature
Volume550
Issue number7676
DOIs
StatePublished - Oct 19 2017
Externally publishedYes

ASJC Scopus subject areas

  • General

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