2. Academic Validation
  3. AMPK phosphorylates WIP1 to promote DNA repair and radioresistance in cancer cells

AMPK phosphorylates WIP1 to promote DNA repair and radioresistance in cancer cells

  • Cell Death Dis. 2025 Nov 28;16(1):864. doi: 10.1038/s41419-025-08141-7.
Manman Lu # 1,  Xiaochuan Dong # 2,  Chunrui Wu 1,  Guisong Wang 1,  Haiyang Wang 1,  Yingli Pan 3,  Yali Qin 4,  Yushuai Song 1,  Hongming Pan 1,  Shenzhi Liu 1,  Kun Zhang 1,  Xuewu Zhang 5 6,  Jing Qu 7 8 9,  Zhenhua Yang 10
Affiliations

Affiliations

  • 1 School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Hubei Key Laboratory of Applied Mathematics, Faculty of Mathematics and Statistics, Hubei University, Wuhan, China.
  • 4 School of Basic Medicine and Forensic Medicine, Henan University of Science & Technology, Luoyang, China.
  • 5 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 6 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, China. [email protected].
  • 7 School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • 8 Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Wuhan, China. [email protected].
  • 9 Key Laboratory of Anesthesiology and Resuscitation (Huazhong University of Science and Technology), Ministry of Education, Wuhan, China. [email protected].
  • 10 School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 41315219 DOI: 10.1038/s41419-025-08141-7
Abstract

Cell metabolism has a profound impact on maintaining genomic stability. AMP-activated protein kinase (AMPK) is a crucial regulator of cell metabolism and the maintenance of genomic stability. There is increasing evidence that AMPK plays a crucial role in the efficient response to DNA damage (DDR). However, the underlying mechanism is still unclear. Here, we show that glucose deprivation rapidly reduces γH2AX levels, a hallmark of DNA damage. We then found that WIP1, rather than PP2A or PP4C, is the primary Phosphatase responsible for dephosphorylating γH2AX under both normal and damaged conditions. Molecular studies have revealed that AMPK directly binds and phosphorylates WIP1 at Thr25 (T25). This action enhances protein stability and the binding ability of WIP1 with γH2AX, likely promoting the enzyme activity of WIP1 and subsequently reducing the level of γH2AX. These processes facilitate DNA damage repair and contribute to the radioresistance of tumor cells. The findings provide experimental evidence of a novel link between metabolic stress and DDR, suggesting that AMPK may promote the resistance of tumor cells to radiation therapy by phosphorylating WIP1.

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