Abuetabh Yasser, Wu H Helena, Al Yousef Habib, Persad Sujata, Schlosser Mary-Pat, Eisenstat David D, Sergi Consolato M, Leng Roger
370 Heritage Medical Research Center, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
Department of Pediatrics, University of Alberta, 11405 - 87 Ave., Edmonton, AB, T6G 1C9, Canada.
Cell Death Discov. 2025 Apr 2;11(1):131. doi: 10.1038/s41420-025-02441-9.
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 dephosphorylation of UBE4B, which stabilizes the activity of the UBE4B protein in response to DNA damage. UBE4B is primarily phosphorylated through ATR-mediated signaling, which reduces its binding affinity with p53, resulting in the accumulation and activation of p53. When Wip1 is inhibited, there is a significant increase in UBE4B phosphorylation, leading to more p53 accumulation and a reduction in cell growth. Therefore, understanding how UBE4B is regulated in cancer cells in response to DNA-damaging agents could help develop new therapeutic strategies to improve the prognosis for cancer patients.
p53肿瘤抑制蛋白通过促进细胞周期停滞、DNA修复、衰老和凋亡等过程，在检测和消除各种致癌威胁中发挥关键作用。UBE4B在正常条件下以及DNA损伤后对p53进行负调控至关重要。在先前的研究中，我们证明UBE4B在DNA损伤时靶向磷酸化的p53进行降解。然而，关于癌症中UBE4B与DNA损伤相关的调控机制尚不清楚。在本研究中，我们表明UBE4B蛋白在DNA损伤时通过磷酸化和去磷酸化机制进行调控。UBE4B的磷酸化降低了其与p53的结合亲和力，导致细胞中p53的积累。Wip1在UBE4B的去磷酸化过程中起关键作用，它在DNA损伤时稳定UBE4B蛋白的活性。UBE4B主要通过ATR介导的信号通路进行磷酸化，这降低了其与p53的结合亲和力，导致p53的积累和激活。当Wip1被抑制时，UBE4B的磷酸化显著增加，导致更多的p53积累和细胞生长减少。因此，了解癌细胞中UBE4B在DNA损伤剂作用下的调控机制，有助于开发新的治疗策略，改善癌症患者的预后。
