L ARP7 Is a BRCA1 Ubiquitinase Substrate and Regulates Genome Stability and Tumorigenesis

Cell Reports

Sun Chen¹  William T. Pu²  Wantao Chen³  Yingwei Chen⁴  Zixuan Li⁴  Weiting Wei⁴  Zeguang Han⁴  Pengyi Yan⁴  Huijing Yu⁴  Huangying Le⁴  Xiaodong Liang⁴  Li Liu⁴  Jiahuan Chen⁴  Kun Sun⁴  Fang Zhang⁴  Xing Ji⁴  Baoxie Ge⁴  Yan Zhang⁵  Shiyan Wang⁶  Bing Zhang⁷  Anyong Xie⁸ 

[1] Harvard Stem Cell Institute, Cambridge, MA 02138, USA;Department of Cardiology, Boston Children’s Hospital, Boston, MA 02115, USA;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;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;Renji-Med Clinical Stem Cell Research Center, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200127, China;School of Life Science and Food Engineering, Huaiyin Institute of Technology, Huaian 223003, China;Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China;Sir Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China;

关键词: BRCA1;    DNA repair;    DNA damage response;    breast cancer;    LARP7;    therapy resistance;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown