The deregulation of ubiquitin-specific protease 7 activity increased DNA replication stress in an in vitro study, which was found to disrupt the DNA repair process during the S phase of the cell cycle.
Aberrant expression of ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, is involved in tumor progression. This is due to altered DNA damage repair and cell proliferation, which also impact tumor response to radiation therapy.
Previous studies have demonstrated the role of USP7 in radiation therapy response via p53-independent and p53-dependent mechanisms. The current study investigated the effects of deregulated expression of USP7 on chromosomal instability and breast cancer prognosis using MDA-MB-231 (triple-negative subtype, p53 mutated) and MCF7 (luminal A subtype, p53 wildtype) cell lines. The findings are published in the journal Biomedicines.
Impact of Deregulated USP7 Activity on Chromosomal Instability and Breast Cancer Survival
High mRNA expression of USP7 was found to be significantly positively associated with an increase in the mutation count compared to tumors with a relatively low expression of USP7. High USP7 expression was also associated with a significant reduction in overall survival in breast cancer patients.
Role of USP7 Activity in DNA Damage and Cellular Survival
The inhibition of USP7 was associated with a dose-dependent decline in the proliferation and clonogenicity of breast cancer cell lines analyzed in the study. Both inhibition and overexpression of USP7 affected the DNA repair process for radiation-induced DNA damage in the S phase.
Altered USP7 Expression and DNA Replication
Deregulation of USP7 was associated with a significant increase in DNA replication stress. This was further related to an increase in the amount of single-stranded DNA, a reduced number of active DNA replication forks, and a reduced incorporation of DNA bases during the replication process. Moreover, USP7 deficiency was related to the accumulation of disrupted DNA repair protein RAD51 in the cells.
USP7 Deregulation and Radiation Therapy Response
The deregulation of USP7 was found to be associated with radiosensitization of the tumor, irrespective of breast cancer cell subtype and the p53 status.
Source:
Vogt, M. F. B., Classen, S., Krause, A. K., Peter, N., Petersen, C., Rothkamm, K., Borgmann, K., & Meyer, F. (2024). USP7 Deregulation Impairs S Phase Specific DNA Repair after Irradiation in Breast Cancer Cells. Biomedicines, 12(4), 762. https://doi.org/10.3390/biomedicines12040762
