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BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing

Author

Listed:
  • Weixing Zhao

    (Yale University School of Medicine)

  • Justin B. Steinfeld

    (Columbia University)

  • Fengshan Liang

    (Yale University School of Medicine
    Section of Hematology-Oncology, Yale University School of Medicine
    Yale University School of Medicine)

  • Xiaoyong Chen

    (Section of Hematology-Oncology, Yale University School of Medicine
    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
    West China Hospital, Sichuan University)

  • 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
    Yale University School of Medicine)

  • Claudia Wiese

    (Colorado State University)

  • Eric C. Greene

    (Columbia University)

  • Patrick Sung

    (Yale University School of Medicine
    Yale University School of Medicine)

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.

Suggested Citation

  • 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-, 2017. "BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing," Nature, Nature, vol. 550(7676), pages 360-365, October.
    • Handle: RePEc:nat:nature:v:550:y:2017:i:7676:d:10.1038_nature24060
    DOI: 10.1038/nature24060
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    Cited by:

    1. George E. Ronson & Katarzyna Starowicz & Elizabeth J. Anthony & Ann Liza Piberger & Lucy C. Clarke & Alexander J. Garvin & Andrew D. Beggs & Celina M. Whalley & Matthew J. Edmonds & James F. J. Beesle, 2023. "Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Qian Zhu & Jinzhou Huang & Hongyang Huang & Huan Li & Peiqiang Yi & Jake A. Kloeber & Jian Yuan & Yuping Chen & Min Deng & Kuntian Luo & Ming Gao & Guijie Guo & Xinyi Tu & Ping Yin & Yong Zhang & Jun , 2021. "RNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Scisung Chung & Mi-Sun Kang & Dauren S. Alimbetov & Gil-Im Mun & Na-Oh Yunn & Yunjin Kim & Byung-Gyu Kim & Minwoo Wie & Eun A. Lee & Jae Sun Ra & Jung-Min Oh & Donghyun Lee & Keondo Lee & Jihan Kim & , 2022. "Regulation of BRCA1 stability through the tandem UBX domains of isoleucyl-tRNA synthetase 1," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Masaru Ito & Asako Furukohri & Kenichiro Matsuzaki & Yurika Fujita & Atsushi Toyoda & Akira Shinohara, 2023. "FIGNL1 AAA+ ATPase remodels RAD51 and DMC1 filaments in pre-meiotic DNA replication and meiotic recombination," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Zhen Wang & Claudia M. Castillo-González & Changjiang Zhao & Chun-Yip Tong & Changhao Li & Songxiao Zhong & Zhiyang Liu & Kaili Xie & Jiaying Zhu & Zhongshou Wu & Xu Peng & Yannick Jacob & Scott D. Mi, 2023. "H3.1K27me1 loss confers Arabidopsis resistance to Geminivirus by sequestering DNA repair proteins onto host genome," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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