2. Academic Validation
  3. C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex

C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex

  • Mol Cell. 2019 Sep 19;75(6):1299-1314.e6. doi: 10.1016/j.molcel.2019.06.023.
Yongtai Bai 1,  Weibin Wang 1,  Siyu Li 1,  Jun Zhan 2,  Hanxiao Li 1,  Meimei Zhao 1,  Xiao Albert Zhou 1,  Shiwei Li 1,  Xiaoman Li 1,  Yanfei Huo 1,  Qinjian Shen 1,  Mei Zhou 1,  Hongquan Zhang 2,  Jianyuan Luo 3,  Patrick Sung 4,  Wei-Guo Zhu 5,  Xingzhi Xu 5,  Jiadong Wang 6
Affiliations

Affiliations

  • 1 Department of Radiation Medicine, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 2 Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 4 Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • 5 Department of Biochemistry and Molecular Biology, Shenzhen University Health Science Center, Shenzhen, 518060, China.
  • 6 Department of Radiation Medicine, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: wangjd@bjmu.edu.cn.
PMID: 31353207 DOI: 10.1016/j.molcel.2019.06.023
Abstract

MRE11 nuclease forms a trimeric complex (MRN) with RAD50 and NBS1 and plays a central role in preventing genomic instability. When DNA double-strand breaks (DSBs) occur, MRN is quickly recruited to the damage site and initiates DNA end resection; accordingly, MRE11 must be tightly regulated to avoid inefficient repair or nonspecific resection. Here, we show that MRE11 and RAD50 form a complex (MRC) with C1QBP, which stabilizes MRE11/RAD50, while inhibiting MRE11 nuclease activity by preventing its binding to DNA or chromatin. Upon DNA damage, ATM phosphorylates MRE11-S676/S678 to quickly dissociate the MRC complex. Either excess or insufficient C1QBP impedes the recruitment of MRE11 to DSBs and impairs the DNA damage response. C1QBP is highly expressed in breast Cancer and positively correlates with MRE11 expression, and the inhibition of C1QBP enhances tumor regression with chemotherapy. By influencing MRE11 at multiple levels, C1QBP is, thus, an important player in the DNA damage response.

Keywords

C1QBP; DNA damage repair; DNA double-strand breaks; MRE11; MRN complex; homologous recombination.

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