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Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis
Dongxue Su, … , Kai Zhang, Lei Shi
Dongxue Su, … , Kai Zhang, Lei Shi
Published September 4, 2018
Citation Information: J Clin Invest. 2018;128(10):4280-4296. https://doi.org/10.1172/JCI120518.
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Research Article Cell biology Oncology Article has an altmetric score of 7

Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis

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Abstract

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.

Authors

Dongxue Su, Shuai Ma, Lin Shan, Yue Wang, Yuejiao Wang, Cheng Cao, Beibei Liu, Chao Yang, Liyong Wang, Shanshan Tian, Xiang Ding, Xinhua Liu, Na Yu, Nan Song, Ling Liu, Shangda Yang, Qi Zhang, Fuquan Yang, Kai Zhang, Lei Shi

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Figure 2

USP7 is recruited to DSB sites.

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USP7 is recruited to DSB sites.
(A) qChIP analysis of USP7 recruitment a...
(A) qChIP analysis of USP7 recruitment around sites of DSBs. HeLa cells stably expressing HA-ER-AsiSI were cultured in the absence or presence of 0.5 μM 4-OHT. qChIP experiments were performed using anti-USP7 or anti-γH2AX antibodies with primers that covered the DNA sequences flanking the AsiSI cutting site and the distal region of the break. γH2AX was used as a positive control. Data represent the mean ± SD of biological triplicate experiments. **P < 0.01, by 2-tailed unpaired Student’s t test. (B) Confocal microscopic analysis of USP7 foci formation upon DSBs. Cells used in A (top) or U2OS cells under x-ray–induced IR (10 Gy, bottom) were preextracted with CSK buffer and then fixed and immunostained with antibodies against USP7 and MDC1 or γH2AX. Scale bars: 10 μm. (C) HeLa cells stably expressing GFP-USP7 were subjected to laser micro-IR and live-cell imaging at the indicated time points. Scale bar: 10 μm. (D) HeLa cells subjected to UVA laser microdissection were fixed and immunostained with antibodies against USP7 and γH2AX or USP7 and MDC1, followed by confocal microscopic analysis. Images are higher-magnification cropped versions of those shown in Supplemental Figure 2B. Scale bars: 10 μm. (E) HeLa cells were transfected with the indicated siRNAs and subjected to UVA laser microdissection. Then, cells were fixed and immunostained with antibodies against γH2AX or USP7, followed by confocal microscopic analysis. Images are higher-magnification cropped versions of those shown in Supplemental Figure 2C. Scale bars: 10 μm. (F) HeLa cells stably expressing GFP-USP7 were transfected with the indicated siRNAs, and cells were then subjected to laser micro-IR and live-cell imaging. Scale bars: 10 μm. (B–F) Representative images from biological triplicate experiments are shown.

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