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

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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Publication Details

Journal
Cell Death and Disease
Published
2025-11-28
DOI
https://doi.org/10.1038/s41419-025-08141-7
Primary Topic
Cancer, Hypoxia, and Metabolism
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Guisong Wang, Zhenhua Yang, Xiaochuan Dong, S.-J. Liu et al.
Cell Death and Disease
Cancer, Hypoxia, and Metabolism
article

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

Guisong Wang, Zhenhua Yang, Xiaochuan Dong, S.-J. Liu, Chao Wu, Yanfeng Pan, Yushuai Song, Manman Lu, Jing Qu, Hongming Pan, Kun Zhang, Haiyang Wang, Xuewu Zhang, Yali Qin
article en

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.

Cell Death and DiseaseVol. 16(1)
Union Hospital (HK), Henan University of Science and Technology (CN), Hubei University of Education (CN), Tongji Hospital (CN), Huazhong University of Science and Technology (CN), Hubei University (CN)
National Natural Science Foundation of China, Chinese Academy of Sciences, Huazhong University of Science and Technology, Natural Science Foundation of Hubei Province, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Openalex Percentile: Top 54%
Cancer, Hypoxia, and Metabolism
DOIOpen Access PDFOpenAlex
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