TRIM24 is critical for the cellular response to DNA double-strand breaks through regulating the recruitment of MRN complex
TRIM24 is critical for the cellular response to DNA double-strand breaks through regulating the recruitment of MRN complex
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TRIM24 通过调节 MRN 复合物的募集，对于细胞对 DNA 双链断裂的反应至关重要
DOI：
10.1038/s41388-022-02580-8
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发表时间：
2022-12-22
期刊：
影响因子：
8
通讯作者：
Fu，Kai
中科院分区：
文献类型：
--
作者：
Wang，Ya;Yao，Yuanbing;Fu，Kai
MRE 11-RAD 50-NBS 1（MRN）复合物在DNA双链断裂（DSB）传感和信号级联的启动中起着至关重要的作用。然而，MRN复合物募集的确切机制尚未阐明。在这里，我们确定了TRIM 24（TRIM 24），一种被认为是在癌症中过表达的癌基因的蛋白质，作为一种新的信号分子，在响应DSB。TRIM 24对于DSB诱导的MRN复合物的募集和下游信号传导的激活是必需的。在缺乏TRIM 24的情况下，MRN介导的DSB修复显着减弱。从机制上讲，TRIM 24被共济失调-毛细血管扩张突变（ATM）磷酸化，然后被募集到DSB位点，促进MRN组分积累到染色质。TRIM 24的耗尽使人肝细胞癌细胞对癌症治疗剂诱导的细胞凋亡敏感，并延缓皮下异种移植肿瘤小鼠模型中的肿瘤生长。总之，我们的数据揭示了TRIM 24通过调节MRN复合物响应DSB的新功能，这表明TRIM 24可能是肿瘤治疗的潜在治疗分子靶点。
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.