Cell Reports (Jun 2024)
The phosphorylation-deubiquitination positive feedback loop of the CHK2-USP7 axis stabilizes p53 under oxidative stress
- Jingwei Liu,
- Liangzi Cao,
- Yubang Wang,
- Yu Zou,
- Qiqiang Guo,
- Shu Chen,
- Bo Jiang,
- Xuan Wu,
- Lixia Zheng,
- Siyi Zhang,
- Songming Lu,
- Keshen Zhou,
- Pengcheng Jiang,
- Yutong Xiao,
- Ruohan Yang,
- Shiyuan Dong,
- Ziwei Li,
- Di Chen,
- Ying Zhang,
- Naijin Zhang,
- Guozhe Sun,
- Chengzhong Xing,
- Xiaoyu Song,
- Zhenning Wang,
- Liu Cao
Affiliations
- Jingwei Liu
- 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
- Liangzi Cao
- 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
- Yubang Wang
- 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
- Yu Zou
- 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
- Qiqiang Guo
- 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
- Shu Chen
- 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
- Bo Jiang
- 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
- Xuan Wu
- 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
- Lixia Zheng
- 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
- Siyi Zhang
- 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
- Songming Lu
- 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
- Keshen Zhou
- 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
- Pengcheng Jiang
- 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
- Yutong Xiao
- 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
- Ruohan Yang
- 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
- Shiyuan Dong
- 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
- Ziwei Li
- 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
- Di Chen
- 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
- Ying Zhang
- 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
- Naijin Zhang
- 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
- Guozhe Sun
- Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang 110001, China; Corresponding author
- Chengzhong Xing
- Department of Anus and Intestine Surgery, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Corresponding author
- Xiaoyu Song
- 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; Corresponding author
- Zhenning Wang
- 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; Corresponding author
- Liu Cao
- 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; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 6
p. 114366
Abstract
Summary: 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.
