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Visualizing and Quantifying Endonuclease-Based Site-Specific DNA Damage
Published on: August 21, 2021
Ubiquitin-specific protease 7 sustains DNA damage response and promotes cervical carcinogenesis
Dongxue Su1, Shuai Ma2, Lin Shan1
1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, 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.
Insights
The ubiquitin-specific protease USP7 stabilizes MDC1, crucial for DNA double-strand break repair. USP7 overexpression in cervical cancer correlates with poor survival, suggesting it as a therapeutic target.
Area of Science:
- Molecular Biology
- Cellular Biology
- Cancer Research
Background:
- DNA double-strand breaks (DSBs) trigger the DNA damage response (DDR).
- The MRE11-RAD50-NBS1 (MRN) complex and mediator of DNA damage checkpoint protein 1 (MDC1) are key regulators of the DDR.
- Mechanisms controlling MRN-MDC1 complex function are not fully understood.
Purpose of the Study:
- To investigate the role of ubiquitin-specific protease 7 (USP7) in regulating the MRN-MDC1 complex and DDR.
- To explore the potential of USP7 as a therapeutic target in cancer.
Main Methods:
- Co-immunoprecipitation to assess protein interactions.
- Western blotting to detect protein levels and ubiquitination.
- siRNA-mediated depletion of USP7.
- Immunofluorescence to visualize protein recruitment at DNA lesions.
- Analysis of patient data for USP7 and MDC1 expression and survival rates.
Main Results:
- USP7 physically associates with the MRN-MDC1 complex.
- USP7 deubiquitinates and stabilizes MDC1, sustaining the DDR.
- USP7 depletion impairs MRN-MDC1 complex engagement and recruitment of 53BP1 and BRCA1.
- USP7 is overexpressed in cervical cancer, correlating with MDC1 levels and poorer patient survival.
- USP7 stabilizes MDC1, promoting cervical cancer cell survival and resistance to genotoxic agents.
Conclusions:
- USP7 plays a critical role in regulating the MRN-MDC1 complex and DDR activity.
- USP7-mediated MDC1 stabilization is important for cervical cancer cell survival.
- USP7 represents a potential therapeutic target for MDC1-proficient cancers.
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