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J Clin Invest. 2018 Oct 1;128(10):4280-4296. doi: 10.1172/JCI120518. Epub 2018 Sep 4.

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

Author information

1
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
2
2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
3
Core Facilities for Molecular Biology, Capital Medical University, Beijing, China.
4
Laboratory of Proteomics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

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.

KEYWORDS:

Cancer; Cell Biology; DNA repair; Oncology; Ubiquitin-proteosome system

PMID:
30179224
PMCID:
PMC6159995
DOI:
10.1172/JCI120518
[Indexed for MEDLINE]
Free PMC Article

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