USP7 reduces the level of nuclear DICER, impairing DNA damage response and promoting cancer progression

• Published in: Molecular oncology Vol. 18; no. 1; pp. 170 - 189
• Main Authors: Liu, Xiaojia, Lu, Runhui, Yang, Qianqian, He, Jianfeng, Huang, Caihu, Cao, Yingting, Zhou, Zihan, Huang, Jiayi, Li, Lian, Chen, Ran, Wang, Yanli, Huang, Jian, Xie, Ruiyu, Zhao, Xian, Yu, Jianxiu
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2024; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; Breast cancer; Cancer; cancer progression; Cancer therapies; Chromatin; Chromatin remodeling; Cytoplasm; DICER; DNA; DNA Damage; DNA Repair; Epigenetic inheritance; Epigenetics; Genetic aspects; Histone H2A; Humans; Ligases; Localization; MDM2; MDM2 protein; MicroRNA; MicroRNAs; miRNA; Neoplasms - drug therapy; Neoplasms - genetics; Nuclear Proteins - genetics; Nucleases; Penicillin; Plasmids; Proteins; Ribonuclease; Ribonuclease III; Ribonuclease III - genetics; Ribonuclease III - metabolism; Transcription factors; Ubiquitin; Ubiquitin carboxy-terminal hydrolase; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism; Ubiquitin-protein ligase; Ubiquitin-Specific Peptidase 7 - genetics; Ubiquitin-Specific Peptidase 7 - metabolism; Ubiquitination; USP7; United States > US; China; MDM2; USP7; DICER; cancer progression; ubiquitination
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13543

Endoribonuclease DICER is an RNase III enzyme that mainly processes microRNAs in the cytoplasm but also participates in nuclear functions such as chromatin remodelling, epigenetic modification and DNA damage repair. The expression of nuclear DICER is low in most human cancers, suggesting a tight regulation mechanism that is not well understood. Here, we found that ubiquitin carboxyl‐terminal hydrolase 7 (USP7), a deubiquitinase, bounded to DICER and reduced its nuclear protein level by promoting its ubiquitination and degradation through MDM2, a newly identified E3 ubiquitin‐protein ligase for DICER. This USP7‐MDM2‐DICER axis impaired histone γ‐H2AX signalling and the recruitment of DNA damage response (DDR) factors, possibly by influencing the processing of small DDR noncoding RNAs. We also showed that this negative regulation of DICER by USP7 via MDM2 was relevant to human tumours using cellular and clinical data. Our findings revealed a new way to understand the role of DICER in malignant tumour development and may offer new insights into the diagnosis, treatment and prognosis of cancers. This study demonstrated that, in the nucleus, USP7 downregulates DICER at the protein level, forming a new regulatory axis that impairs DNA damage response and then promotes tumour growth. Additionally, MDM2 is identified as a new ubiquitin E3 ligase of DICER, indirectly mediating the negative regulation of DICER by USP7.