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

doi:10.1038/nature24060

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

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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 language	English (US)
Article number	nature24060
Journal	Nature
Volume	550
Issue number	7676
DOIs	https://doi.org/10.1038/nature24060
State	Published - Oct 19 2017
Externally published	Yes

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Zhao, W., Steinfeld, J. B., Liang, F., Chen, X., Maranon, D. G., Jian Ma, C., Kwon, Y., Rao, T., Wang, W., Sheng, C., Song, X., Deng, Y., Jimenez-Sainz, J., Lu, L., Jensen, R. B., Xiong, Y., Kupfer, G. M., Wiese, C., Greene, E. C., & Sung, P. (2017). BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature, 550(7676), Article nature24060. https://doi.org/10.1038/nature24060

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title = "BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing",

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.",

author = "Weixing Zhao and Steinfeld, {Justin B.} and Fengshan Liang and Xiaoyong Chen and Maranon, {David G.} and {Jian Ma}, Chu and Youngho Kwon and Timsi Rao and Weibin Wang and Chen Sheng and Xuemei Song and Yanhong Deng and Judit Jimenez-Sainz and Lucy Lu and Jensen, {Ryan B.} and Yong Xiong and Kupfer, {Gary M.} and Claudia Wiese and Greene, {Eric C.} and Patrick Sung",

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doi = "10.1038/nature24060",

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T1 - BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing

AU - Zhao, Weixing

AU - Steinfeld, Justin B.

AU - Liang, Fengshan

AU - Chen, Xiaoyong

AU - Maranon, David G.

AU - Jian Ma, Chu

AU - Kwon, Youngho

AU - Rao, Timsi

AU - Wang, Weibin

AU - Sheng, Chen

AU - Song, Xuemei

AU - Deng, Yanhong

AU - Jimenez-Sainz, Judit

AU - Lu, Lucy

AU - Jensen, Ryan B.

AU - Xiong, Yong

AU - Kupfer, Gary M.

AU - Wiese, Claudia

AU - Greene, Eric C.

AU - Sung, Patrick

PY - 2017/10/19

Y1 - 2017/10/19

N2 - 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.

AB - 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.

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BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing

Abstract

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