LARP7 Is a BRCA1 Ubiquitinase Substrate and Regulates Genome Stability and Tumorigenesis
LARP7 Is a BRCA1 Ubiquitinase Substrate and Regulates Genome Stability and Tumorigenesis
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L ARP7 是 BRCA1 泛素酶底物，调节基因组稳定性和肿瘤发生
DOI：
10.1016/j.celrep.2020.107974
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发表时间：
2020
期刊：
影响因子：
8.8
通讯作者：
Zhang Bing
中科院分区：
文献类型：
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作者：
Zhang Fang;Yan Pengyi;Yu Huijing;Le Huangying;Li Zixuan;Chen Jiahuan;Liang Xiaodong;Wang Shiyan;Wei Weiting;Liu Li;Zhang Yan;Ji Xing;Xie Anyong;Chen Wantao;Han Zeguang;Pu William T.;Chen Sun;Chen Yingwei;Sun Kun;Ge Baoxue;Zhang Bing
减弱的DNA修复导致基因组不稳定和肿瘤发生。BRCA 1/BARD 1是最著名的肿瘤抑制因子，其促进同源重组（HR）并阻滞细胞周期。然而，它仍然是模糊的，是否以及如何E3连接酶活性调节HR。在这里，我们证明，基因毒性应激后，BRCA 1与BARD 1一起催化LARP 7，已知控制RNAPII暂停的7SK RNA结合蛋白上的K48聚泛素化，从而通过26 S泛素-蛋白酶体途径降解它。LARP 7的缺失抑制CDK 1复合物的表达，使细胞在G2/M DNA损伤检查点停滞，并减少BRCA 2磷酸化，从而促进RAD 51募集到受损DNA以增强HR。重要的是，在乳腺癌患者中观察到的LARP 7缺失导致体外和体内放化疗抵抗。总之，本研究揭示了BRCA 1/BARD 1控制HR和细胞周期的机制，并强调LARP 7是癌症预防和治疗的潜在靶点。
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 bothin vitroandin 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.