UBE4B Phosphorylation is Essential to Stabilize p53 in Response to DNA Damage

Abstract The tumor suppressor p53 plays a fundamental role in the detection and eradication of different oncogenic insults by promoting cell cycle arrest, DNA repair, senescence, and apoptosis. UBE4B is crucial for negatively regulating p53 during homeostasis and after DNA damage. We previously demonstrated that UBE4B targets phosphorylated p53 for degradation in response to DNA damage. However, the regulation of UBE4B in response to DNA damage in cancer is unknown. Here, we show that the UBE4B protein is regulated through a phosphorylation/dephosphorylation mechanism in response to DNA damage. The phosphorylation of UBE4B decreased its affinity binding to p53 and led to the accumulation of p53. Furthermore, Wip1 dephosphorylation of UBE4B stabilizes the activity of the UBE4B protein in response to DNA damage. UBE4B is predominantly phosphorylated by upstream ATR-mediated signaling, which decreasesaffinity binding of UBE4B-p53 and leads to the accumulation and activation of p53. Inhibition of Wip1 led to a significant increase in UBE4B phosphorylation, accumulation of p53, and inhibition of cell growth. Understanding how UBE4B is regulated in cancer cells in response to DNA-damaging agents may lead to the development of novel therapeutic strategies to improve the prognosis of cancer patients.