@article{ccbe0237a9684cbca7b7b1038295361f,
title = "C1QBP Promotes Homologous Recombination by Stabilizing MRE11 and Controlling the Assembly and Activation of MRE11/RAD50/NBS1 Complex",
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",
author = "Yongtai Bai and Weibin Wang and Siyu Li and Jun Zhan and Hanxiao Li and Meimei Zhao and Zhou, {Xiao Albert} and Shiwei Li and Xiaoman Li and Yanfei Huo and Qinjian Shen and Mei Zhou and Hongquan Zhang and Jianyuan Luo and Patrick Sung and Zhu, {Wei Guo} and Xingzhi Xu and Jiadong Wang",
note = "Funding Information: We thank Drs. Mo Li (Peking University Third Hospital), Huadong Pei (Beijing Institute of Lifeomics), and Xiaofeng Zheng (Peking University) for reagents and technical help. We thank all members of the Wang laboratory for insightful discussion and technical assistance. This study was supported by the National Key R&D Program of China ( 2016YFC1302100 and 2017YFA0503900 ), the National Natural Science Foundation of China ( 81672981 , 81872282 , 81621063 , 81803017 , and 81661128008 ), NIH ( RO1ES007061 ), Beijing Municipal Natural Science Foundation ( 7182082 ), Peking University ( BMU20140367 ), and the Young Talent 1000 Project ( QNQR201602 ). Funding Information: We thank Drs. Mo Li (Peking University Third Hospital), Huadong Pei (Beijing Institute of Lifeomics), and Xiaofeng Zheng (Peking University) for reagents and technical help. We thank all members of the Wang laboratory for insightful discussion and technical assistance. This study was supported by the National Key R&D Program of China (2016YFC1302100 and 2017YFA0503900), the National Natural Science Foundation of China (81672981, 81872282, 81621063, 81803017, and 81661128008), NIH (RO1ES007061), Beijing Municipal Natural Science Foundation (7182082), Peking University (BMU20140367), and the Young Talent 1000 Project (QNQR201602). Conceptualization, Y.B. W.W. and J.W.; Investigation, Y.B. W.W. S.L. J.Z. H.L. M. Zhao, S.L. P.S. X.L. and J.W.; Writing, Y.B. W.W. and J.W.; Resources, Q.S. and M. Zhou; Drawing, Y.H.; Discussion, X.A.Z. H.Z. J.L. W.G.-Z. and X.X.; Supervision, W.W. and J.W. The authors declare no competing interests.",
year = "2019",
month = sep,
day = "19",
doi = "10.1016/j.molcel.2019.06.023",
language = "English (US)",
volume = "75",
pages = "1299--1314.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}