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

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 W. Mutter () and Jian Yuan ()
Additional contact information
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
Somaira Nowsheen: Mayo Clinic School of Medicine and Mayo Clinic Graduate School of Biomedical Sciences, 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
Bo Qin: Mayo Clinic
Kuntian Luo: Mayo Clinic
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

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16443-x

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