Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis
Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis
复制标题
泛素特异性蛋白酶 7 维持 DNA 损伤反应并促进宫颈癌发生。
DOI：
10.1172/jci120518
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发表时间：
2018-10-01
影响因子：
15.9
通讯作者：
Shi, Lei
中科院分区：
文献类型：
--
作者：
Su, Dongxue;Ma, Shuai;Shi, Lei
DNA 双链断裂 (DSB) 识别、信号传导和修复的核心是 MRE11-RAD50-NBS1 (MRN) 复合物和 DNA 损伤检查点蛋白 1 (MDC1) 的介导物，它们之间的相互作用对于 DNA 损伤反应 (DDR) 的启动和放大至关重要。控制这种分子机器功能的内在规则仍有待研究。我们在此报告，泛素特异性蛋白酶 USP7 与 MRN-MDC1 复合物物理相关，并且 MRN-MDC1 复合物充当 USP7 有效去泛素化和稳定 MDC1 的平台，从而维持 DDR。因此，USP7 的缺失会损害 MRN-MDC1 复合物的结合，以及随后在 DNA 损伤处招募下游因子 p53 结合蛋白 1 (53BP1) 和乳腺癌蛋白 1 (BRCA1)。值得注意的是，USP7在宫颈癌中过度表达，其表达水平与MDC1呈正相关，导致宫颈癌患者的生存率较差。我们证明 USP7 介导的 MDC1 稳定可促进宫颈癌细胞存活并赋予细胞对基因毒性损伤的抵抗力。总之，我们的研究揭示了 USP7 在调节 MRN-MDC1 复合物的功能和 DDR 活性中的作用，支持将 USP7 作为 MDC1 丰富的癌症的潜在治疗靶点。
Central to the recognition, signaling, and repair of DNA double-strand breaks (DSBs) are the MRE11-RAD50-NBS1 (MRN) complex and mediator of DNA damage checkpoint protein 1 (MDC1), the interplay of which is essential for initiation and amplification of the DNA damage response (DDR). The intrinsic rule governing the regulation of the function of this molecular machinery remains to be investigated. We report here that the ubiquitin-specific protease USP7 was physically associated with the MRN-MDC1 complex and that the MRN-MDC1 complex acted as a platform for USP7 to efficiently deubiquitinate and stabilize MDC1, thereby sustaining the DDR. Accordingly, depletion of USP7 impaired the engagement of the MRN-MDC1 complex and the consequent recruitment of the downstream factors p53-binding protein 1 (53BP1) and breast cancer protein 1 (BRCA1) at DNA lesions. Significantly, USP7 was overexpressed in cervical cancer, and the level of its expression positively correlated with that of MDC1 and worse survival rates for patients with cervical cancer. We demonstrate that USP7-mediated MDC1 stabilization promoted cervical cancer cell survival and conferred cellular resistance to genotoxic insults. Together, our study reveals a role for USP7 in regulating the function of the MRN-MDC1 complex and activity of the DDR, supporting the pursuit of USP7 as a potential therapeutic target for MDC1-proficient cancers.