2. Academic Validation
  3. The bromodomain containing protein BRD-9 orchestrates RAD51-RAD54 complex formation and regulates homologous recombination-mediated repair

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

  • Nat Commun. 2020 May 26;11(1):2639. doi: 10.1038/s41467-020-16443-x.
Qin Zhou # 1,  Jinzhou Huang # 1,  Chao Zhang # 1,  Fei Zhao 1,  Wootae Kim 1,  Xinyi Tu 1,  Yong Zhang 1 2,  Somaira Nowsheen 3 4,  Qian Zhu 5,  Min Deng 1,  Yuping Chen 5 6,  Bo Qin 1,  Kuntian Luo 1 5 6,  Baohua Liu 7,  Zhenkun Lou 1,  Robert W Mutter 8,  Jian Yuan 9 10
Affiliations

Affiliations

  • 1 Department of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
  • 2 Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 3 Mayo Medical Scientist Training Program, Mayo Clinic School of Medicine and Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, 55905, USA.
  • 4 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, 55905, USA.
  • 5 Research Center for Translational Medicine, East Hospital, Tongji University School of medicine, Shanghai, 200120, China.
  • 6 Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
  • 7 Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen, 518055, China.
  • 8 Department of Radiation Oncology, Mayo Clinic, Rochester, MN, 55905, USA. [email protected].
  • 9 Research Center for Translational Medicine, East Hospital, Tongji University School of medicine, Shanghai, 200120, China. [email protected].
  • 10 Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai, 200120, China. [email protected].
  • # Contributed equally.
PMID: 32457312 DOI: 10.1038/s41467-020-16443-x
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.

Figures