Cell Reports (Jul 2020)
L ARP7 Is a BRCA1 Ubiquitinase Substrate and Regulates Genome Stability and Tumorigenesis
- Fang Zhang,
- Pengyi Yan,
- Huijing Yu,
- Huangying Le,
- Zixuan Li,
- Jiahuan Chen,
- Xiaodong Liang,
- Shiyan Wang,
- Weiting Wei,
- Li Liu,
- Yan Zhang,
- Xing Ji,
- Anyong Xie,
- Wantao Chen,
- Zeguang Han,
- William T. Pu,
- Sun Chen,
- Yingwei Chen,
- Kun Sun,
- Baoxie Ge,
- Bing Zhang
Affiliations
- Fang Zhang
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Pengyi Yan
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Huijing Yu
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Huangying Le
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Zixuan Li
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Jiahuan Chen
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Xiaodong Liang
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Shiyan Wang
- School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian 223003, China
- Weiting Wei
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Li Liu
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Yan Zhang
- Renji-Med Clinical Stem Cell Research Center, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China
- Xing Ji
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Anyong Xie
- Sir Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Wantao Chen
- Department of Oral and Maxillofacial Head and Neck Oncology, Shanghai Key Laboratory of Stomatology, Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, China
- Zeguang Han
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- William T. Pu
- Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA
- Sun Chen
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Yingwei Chen
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Kun Sun
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
- Baoxie Ge
- Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
- Bing Zhang
- Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China; Corresponding author
- Journal volume & issue
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Vol. 32,
no. 4
p. 107974
Abstract
Summary: Attenuated DNA repair leads to genomic instability and tumorigenesis. BRCA1/BARD1 are the best-known tumor suppressors that promote homology recombination (HR) and arrest cell cycle. However, it remains ambiguous whether and how their E3 ligase activity regulates HR. Here, we demonstrate that upon genotoxic stress, BRCA1 together with BARD1 catalyzes the K48 polyubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degrades it through the 26S ubiquitin-proteasome pathway. Depleting LARP7 suppresses the expression of CDK1 complex, arrests the cell at the G2/M DNA damage checkpoint, and reduces BRCA2 phosphorylation, which thereby facilitates RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast cancer patients leads to chemoradiotherapy resistance both in vitro and in vivo. Altogether, this study unveils a mechanism by which BRCA1/BARD1 control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy.
