LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis
LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis
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 at G2/M checkpoint. As E3 ubiquitin ligases, their ubiquitinase activity has been known to involve in the HR and tumor suppression, but the mechanism remains ambiguous. Here, we demonstrated upon genotoxic stress, BRCA1 together with BARD1 catalyzed the K48 ployubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degraded it through 26S ubiquitin-proteasome pathway. Depleting LARP7 suppressed the expression of CDK1 complex, arrested cell at G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation which thereby facilitated RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast patients lead to the chemoradiotherapy resistance both in vitro and in vivo. Together, this study unveils a mechanism by which BRCA1/BARD1 utilizes their E3 ligase activity to control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy. HighlightsDNA damage response downregulates LARP7 through BRCA1/BARD1BRCA1/BARD1 catalyzes the K48 polyubiquitination on LARP7LARP7 promotes G2/M cell cycle transition and tumorigenesis via CDK1 complexLARP7 disputes homology-directed repair that leads to tumor therapy resistance
Yan Pengyi、Liang Xiaodong、Wang Shiyan、Liu Li、Zhang Yan、Ji Xing、Xie Anyong、Chen Wantao、Chen Sun、Zhang Bing、Zhang Fang、Yu Huijing、Han Zeguang、Chen Jiahuan、Le Huangying、Pu William T.、Sun Kun、li Zixuan、Wei Weiting、Chen Yingwei、Ge Baoxie
Xin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversitySchool of Life Science and Food Engineering, Huaiyin Institute of TechnologyXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityRenji-Med Clinical Stem Cell Research Center, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversitySir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of MedicineDepartment of Oral and Maxillofacial Head and Neck Oncology, Shanghai Key Laboratory of Stomatology, Ninth People?ˉs Hospital, Shanghai Jiao Tong University, School of Medicine. Shanghai 200011Xin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityDepartment of Cardiology, Boston Children?ˉs Hospital||Harvard Stem Cell InstituteXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityXin Hua Hospital, Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong UniversityShanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine||Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine
肿瘤学基础医学分子生物学
Yan Pengyi,Liang Xiaodong,Wang Shiyan,Liu Li,Zhang Yan,Ji Xing,Xie Anyong,Chen Wantao,Chen Sun,Zhang Bing,Zhang Fang,Yu Huijing,Han Zeguang,Chen Jiahuan,Le Huangying,Pu William T.,Sun Kun,li Zixuan,Wei Weiting,Chen Yingwei,Ge Baoxie.LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/808535.点此复制
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