biostudies-literatureLu MNatural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)National Natural Science Foundation of China (National Science Foundation of China)864https://www.ebi.ac.uk/biostudies/studies/S-EPMC12663271biostudies-literatureUnknown16(1)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 promotiCell death & diseaseAMPK phosphorylates WIP1 to promote DNA repair and radioresistance in cancer cells.PMC126632718220333382070171822220022022CFB07882003093Pan YZhang KDong XWu CQu JQin YWang GWang HLiu SPan HLu MYang ZZhang XSong YfalseAMPK 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 promoti2025-01-01T00:00:00Z2025 Nov2026-06-05T21:42:25.879Z2026-05-22T03:15:26.531ZS-EPMC126632714131521910.1038/s41419-025-08141-7