biostudies-literatureAbuetabh YCanadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of CanadaGouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training CentreGouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre)Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology)131https://www.ebi.ac.uk/biostudies/studies/S-EPMC11965332biostudies-literatureUnknown11(1)The p53 tumor suppressor protein plays a crucial role in detecting and eliminating various oncogenic threats by promoting processes such as cell cycle arrest, DNA repair, senescence, and apoptosis. UBE4B is essential for negatively regulating p53 during normal conditions and following DNA damage. In previous studies, we demonstrated that UBE4B targets phosphorylated p53 for degradation in response to DNA damage. However, the regulation of UBE4B in relation to DNA damage in cancer is not well understood. In this study, we show that the UBE4B protein is regulated through a phosphorylation and dephosphorylation mechanism in response to DNA damage. Phosphorylation of UBE4B reduces its binding affinity to p53, leading to an accumulation of p53 in the cell. Wip1 plays a crucial role in the dephoCell death discoveryDeciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage.PMC1196533206582115177Al Yousef HPersad SAbuetabh YSergi CMSchlosser MPLeng REisenstat DDWu HHfalseDeciphering UBE4B phosphorylation dynamics: a key mechanism in p53 accumulation and cancer cell response to DNA damage.The p53 tumor suppressor protein plays a crucial role in detecting and eliminating various oncogenic threats by promoting processes such as cell cycle arrest, DNA repair, senescence, and apoptosis. UBE4B is essential for negatively regulating p53 during normal conditions and following DNA damage. In previous studies, we demonstrated that UBE4B targets phosphorylated p53 for degradation in response to DNA damage. However, the regulation of UBE4B in relation to DNA damage in cancer is not well understood. In this study, we show that the UBE4B protein is regulated through a phosphorylation and dephosphorylation mechanism in response to DNA damage. Phosphorylation of UBE4B reduces its binding affinity to p53, leading to an accumulation of p53 in the cell. Wip1 plays a crucial role in the depho2025-01-01T00:00:00Z2025 Apr2026-06-01T19:20:28.793Z2025-06-26T03:06:03.409ZS-EPMC119653324017534610.1038/s41420-025-02441-9