Wang Ya, Yao Yuanbing, Wei Qunhui, Long Shichao, Chen Yuqiao, Xie Jinru, Tan Rong, Jiang Wei, Zhang Qian, Wu Dongbo, Xiao Shuai, Wan Fengyi, Fu Kai
Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410008, Hunan, China.
Oncogene. 2023 Feb;42(8):586-600. doi: 10.1038/s41388-022-02580-8. Epub 2022 Dec 22.
The MRE11-RAD50-NBS1 (MRN) complex plays a crucial role in DNA double-strand breaks (DSBs) sensing and initiation of signaling cascades. However, the precise mechanisms by which the recruitment of MRN complex is regulated has yet to be elucidated. Here, we identified TRIpartite motif-containing protein 24 (TRIM24), a protein considered as an oncogene overexpressed in cancers, as a novel signaling molecule in response to DSBs. TRIM24 is essential for DSBs-induced recruitment of MRN complex and activation of downstream signaling. In the absence of TRIM24, MRN mediated DSBs repair is remarkably diminished. Mechanistically, TRIM24 is phosphorylated by ataxia-telangiectasia mutated (ATM) and then recruited to DSBs sites, facilitating the accumulation of the MRN components to chromatin. Depletion of TRIM24 sensitizes human hepatocellular carcinoma cells to cancer therapy agent-induced apoptosis and retards the tumor growth in a subcutaneous xenograft tumor mouse model. Together, our data reveal a novel function of TRIM24 in response to DSBs through regulating the MRN complex, which suggests that TRIM24 may be a potential therapeutic molecular target for tumor treatment.
MRE11-RAD50-NBS1（MRN）复合物在DNA双链断裂（DSB）的感知及信号级联反应的启动中发挥着关键作用。然而，MRN复合物募集的调控精确机制尚未阐明。在此，我们鉴定出含三联基序蛋白24（TRIM24），一种在癌症中被视为癌基因且过表达的蛋白，作为响应DSB的新型信号分子。TRIM24对于DSB诱导的MRN复合物募集及下游信号激活至关重要。在缺乏TRIM24时，MRN介导的DSB修复显著减少。机制上，TRIM24被共济失调毛细血管扩张症突变蛋白（ATM）磷酸化，然后被募集至DSB位点，促进MRN组分在染色质上的积累。在皮下异种移植瘤小鼠模型中，TRIM24的缺失使人类肝癌细胞对癌症治疗药物诱导的凋亡敏感，并延缓肿瘤生长。总之，我们的数据揭示了TRIM24通过调节MRN复合物响应DSB的新功能，这表明TRIM24可能是肿瘤治疗的潜在治疗分子靶点。
