The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of the Ministry of Public Health, Key Laboratory of Medical Cell Biology of the Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of the Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging-Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China; Department of Anus and Intestine Surgery, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, China.
The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China; Key Laboratory of Cell Biology of the Ministry of Public Health, Key Laboratory of Medical Cell Biology of the Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of the Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging-Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China.
Cell Rep. 2024 Jun 25;43(6):114366. doi: 10.1016/j.celrep.2024.114366. Epub 2024 Jun 15.
p53 regulates multiple signaling pathways and maintains cell homeostasis under conditions of DNA damage and oxidative stress. Although USP7 has been shown to promote p53 stability via deubiquitination, the USP7-p53 activation mechanism has remained unclear. Here, we propose that DNA damage induces reactive oxygen species (ROS) production and activates ATM-CHK2, and CHK2 then phosphorylates USP7 at S168 and T231. USP7 phosphorylation is essential for its deubiquitination activity toward p53. USP7 also deubiquitinates CHK2 at K119 and K131, increasing CHK2 stability and creating a positive feedback loop between CHK2 and USP7. Compared to peri-tumor tissues, thyroid cancer and colon cancer tissues show higher CHK2 and phosphorylated USP7 (S168, T231) levels, and these levels are positively correlated. Collectively, our results uncover a phosphorylation-deubiquitination positive feedback loop involving the CHK2-USP7 axis that supports the stabilization of p53 and the maintenance of cell homeostasis.
p53 调节多种信号通路，并在 DNA 损伤和氧化应激条件下维持细胞内稳态。虽然 USP7 已被证明通过去泛素化作用促进 p53 稳定性，但 USP7-p53 激活机制仍不清楚。在这里，我们提出 DNA 损伤诱导活性氧（ROS）的产生并激活 ATM-CHK2，然后 CHK2 将 USP7 在 S168 和 T231 位点磷酸化。USP7 磷酸化对于其对 p53 的去泛素化活性至关重要。USP7 还在 K119 和 K131 处去泛素化 CHK2，增加 CHK2 的稳定性，并在 CHK2 和 USP7 之间形成正反馈回路。与肿瘤周围组织相比，甲状腺癌和结肠癌组织显示出更高的 CHK2 和磷酸化 USP7（S168、T231）水平，并且这些水平呈正相关。总之，我们的结果揭示了涉及 CHK2-USP7 轴的磷酸化-去泛素化正反馈回路，该回路支持 p53 的稳定和细胞内稳态的维持。
