VprBP（也称为DCAF1）是一种最近发现的激酶，在癌细胞中过度表达，是表观遗传基因沉默和肿瘤发生的主要决定因素。 VprBP在驱动靶基因失活方面的作用主要归因于其介导组蛋白H2A磷酸化的能力。然而，VprBP是否也磷酸化非组蛋白蛋白质，以及这些磷酸化事件是否驱动致癌信号通路尚未探究。在这里，我们报告了VprBP通过直接与p53的C末端结构域相互作用催化p53的丝氨酸367磷酸化（S367p），是减弱p53转录和生长抑制活性的关键因素。VprBP介导的S367p机制上抑制了p53的功能，在促进p53蛋白酶降解的同时，因为阻止p53S367p会增加p53蛋白质水平，从而增强p53转录激活。此外，乙酰化p53阻止了VprBP-p53相互作用对于防止p53S367p以及在DNA损伤响应时增强p53功能至关重要。总之，我们的发现确定了VprBP介导的S367p作为p53功能的负调节因子，并识别了一种以往未被描述的S367p调节p53稳定性的机制。 © 2023.作者。

VprBP (also known as DCAF1) is a recently identified kinase that is overexpressed in cancer cells and serves as a major determinant for epigenetic gene silencing and tumorigenesis. The role of VprBP in driving target gene inactivation has been largely attributed to its ability to mediate histone H2A phosphorylation. However, whether VprBP also phosphorylates non-histone proteins and whether these phosphorylation events drive oncogenic signaling pathways have not been explored. Here we report that serine 367 phosphorylation (S367p) of p53 by VprBP is a key player in attenuating p53 transcriptional and growth suppressive activities. VprBP catalyzes p53S367p through a direct interaction with the C-terminal domain of p53. Mechanistically, VprBP-mediated S367p inhibits p53 function in the wake of promoting p53 proteasomal degradation, because blocking p53S367p increases p53 protein levels, thereby enhancing p53 transactivation. Furthermore, abrogation of VprBP-p53 interaction by p53 acetylation is critical for preventing p53S367p and potentiating p53 function in response to DNA damage. Together, our findings establish VprBP-mediated S367p as a negative regulator of p53 function and identify a previously uncharacterized mechanism by which S367p modulates p53 stability.© 2023. The Author(s).