Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, China.
Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, China.
Mol Oncol. 2024 Jan;18(1):170-189. doi: 10.1002/1878-0261.13543. Epub 2023 Nov 2.
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.
内切核糖核酸酶 DICER 是一种 RNase III 酶，主要在细胞质中加工 microRNAs，但也参与核功能，如染色质重塑、表观遗传修饰和 DNA 损伤修复。大多数人类癌症中核 DICER 的表达较低，表明存在一种尚未充分了解的严格调控机制。在这里，我们发现泛素羧基末端水解酶 7（USP7），一种去泛素酶，通过促进其通过新鉴定的 DICER E3 泛素蛋白连接酶 MDM2 的泛素化和降解，与 DICER 结合并降低其核蛋白水平。该 USP7-MDM2-DICER 轴通过影响小 DDR 非编码 RNA 的加工，损害了组蛋白 γ-H2AX 信号和 DDR 因子的募集。我们还使用细胞和临床数据表明，USP7 通过 MDM2 对 DICER 的这种负调控与人类肿瘤有关。我们的研究结果揭示了 DICER 在恶性肿瘤发展中的作用的新途径，并可能为癌症的诊断、治疗和预后提供新的见解。
