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The bromodomain containing protein BRD-9 orchestrates RAD51–RAD54 complex formation and regulates homologous recombination-mediated repair

Author

Listed:
  • Qin Zhou

    (Mayo Clinic)

  • Jinzhou Huang

    (Mayo Clinic)

  • Chao Zhang

    (Mayo Clinic)

  • Fei Zhao

    (Mayo Clinic)

  • Wootae Kim

    (Mayo Clinic)

  • Xinyi Tu

    (Mayo Clinic)

  • Yong Zhang

    (Mayo Clinic
    Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology)

  • Somaira Nowsheen

    (Mayo Clinic School of Medicine and Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic
    Mayo Clinic)

  • Qian Zhu

    (Research Center for Translational Medicine, East Hospital, Tongji University School of medicine)

  • Min Deng

    (Mayo Clinic)

  • Yuping Chen

    (Research Center for Translational Medicine, East Hospital, Tongji University School of medicine
    Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine)

  • Bo Qin

    (Mayo Clinic)

  • Kuntian Luo

    (Mayo Clinic
    Research Center for Translational Medicine, East Hospital, Tongji University School of medicine
    Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine)

  • Baohua Liu

    (School of Basic Medical Sciences, Shenzhen University Health Science Center)

  • Zhenkun Lou

    (Mayo Clinic)

  • Robert W. Mutter

    (Mayo Clinic)

  • Jian Yuan

    (Research Center for Translational Medicine, East Hospital, Tongji University School of medicine
    Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine)

Abstract

Homologous recombination (HR) is important for error-free DNA double strand break repair and maintenance of genomic stability. However, upregulated HR is also used by cancer cells to promote therapeutic resistance. Therefore, inducing HR deficiency (HRD) is a viable strategy to sensitize HR proficient cancers to DNA targeted therapies in order to overcome therapeutic resistance. A bromodomain containing protein, BRD9, was previously reported to regulate chromatin remodeling and transcription. Here, we discover that following DNA damage, the bromodomain of BRD9 binds acetylated K515 on RAD54 and facilitates RAD54’s interaction with RAD51, which is essential for HR. BRD9 is overexpressed in ovarian cancer and depleting BRD9 sensitizes cancer cells to olaparib and cisplatin. In addition, inhibitor of BRD9, I-BRD9, acts synergistically with olaparib in HR-proficient cancer cells. Overall, our results elucidate a role for BRD9 in HR and identify BRD9 as a potential therapeutic target to promote synthetic lethality and overcome chemoresistance.

Suggested Citation

  • Qin Zhou & Jinzhou Huang & Chao Zhang & Fei Zhao & Wootae Kim & Xinyi Tu & Yong Zhang & Somaira Nowsheen & Qian Zhu & Min Deng & Yuping Chen & Bo Qin & Kuntian Luo & Baohua Liu & Zhenkun Lou & Robert , 2020. "The bromodomain containing protein BRD-9 orchestrates RAD51–RAD54 complex formation and regulates homologous recombination-mediated repair," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16443-x
    DOI: 10.1038/s41467-020-16443-x
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    Cited by:

    1. Indu Kohaar & Xijun Zhang & Shyh-Han Tan & Darryl Nousome & Kevin Babcock & Lakshmi Ravindranath & Gauthaman Sukumar & Elisa Mcgrath-Martinez & John Rosenberger & Camille Alba & Amina Ali & Denise You, 2022. "Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes," Nature Communications, Nature, vol. 13(1), pages 1-9, December.

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