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Nature. 2017 Oct 19;550(7676):360-365. doi: 10.1038/nature24060. Epub 2017 Oct 4.

BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing.

Author information

1
Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
2
Department of Biochemistry & Molecular Biophysics, Columbia University, New York, New York 10032, USA.
3
Section of Hematology-Oncology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
4
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
5
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.
6
Yale Center for Analytical Sciences, Yale School of Public Health, New Haven, Connecticut, USA.
7
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.

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.

PMID:
28976962
PMCID:
PMC5800781
DOI:
10.1038/nature24060
[Indexed for MEDLINE]
Free PMC Article

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