<scp>E6</scp> ‐associated protein induces ubiquitin‐dependent proteasomal degradation of p53 phosphorylated at Ser‐15 in response to genotoxic stress

The tumor suppressor p53 is normally maintained at low levels through MDM2-mediated degradation; however, this regulation becomes ineffective upon DNA damage, leading to p53 phosphorylation and accumulation. This study shows that E6-associated protein (E6AP) provides an alternative regulatory pathway during genotoxic stress. Unlike MDM2, E6AP can effectively decrease p53 levels in HepG2 cells exposed to DNA-damaging agents, such as etoposide. Additionally, E6AP specifically targets p53 phosphorylated at serine-15, promoting its proteasomal degradation, whereas MDM2 cannot. This phosphorylation-dependent regulation by E6AP helps maintain p53 at appropriate levels during mild DNA damage, preventing excessive accumulation that could threaten cell survival, while still allowing for necessary stress responses. Impact statement The mechanism by which p53 is negatively regulated under genotoxic stress is largely unknown. E6-associated protein (E6AP), unlike MDM2, downregulates p53 levels following exposure to etoposide. E6AP specifically targets p53 phosphorylated at Ser-15. This mechanism prevents excessive accumulation of p53 that could otherwise reach lethal levels.