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
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C1QBP 通过稳定 MRE11 并控制 MRE11/RAD50/NBS1 复合物的组装和激活来促进同源重组
DOI：
10.1016/j.molcel.2019.06.023
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发表时间：
2019-09-19
期刊：
影响因子：
16
通讯作者：
Wang, Jiadong
中科院分区：
文献类型：
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作者：
Bai, Yongtai;Wang, Weibin;Wang, Jiadong
MRE11核酸酶与RAD50和NBS1形成三聚体复合物（MRN），在防止基因组不稳定中起核心作用。当DNA双链断裂（DSBs）发生时，MRN迅速被招募到损伤部位并启动DNA末端切除；因此，必须严格调控MRE11，以避免无效修复或非特异性切除。在这里，我们发现MRE11和RAD50与C1QBP形成复合物（MRC），该复合物稳定了MRE11/RAD50，同时通过阻止MRE11与DNA或染色质结合来抑制MRE11核酸酶的活性。在DNA损伤时，ATM使MRE11-S676/S678磷酸化，以快速解离MRC复合物。过量或不足的C1QBP都会阻碍MRE11向dsb的募集，并损害DNA损伤反应。C1QBP在乳腺癌中高表达，与MRE11表达呈正相关，抑制C1QBP可促进肿瘤随化疗的消退。通过在多个水平上影响MRE11， C1QBP在DNA损伤反应中起着重要作用。
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.