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.

VprBP（也称为 DCAF1）是最近发现的一种激酶，它在癌细胞中过表达，是表观遗传基因沉默和肿瘤发生的主要决定因素。VprBP 在驱动靶基因失活中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以及这些磷酸化事件是否驱动致癌信号通路尚未得到探索。在这里，我们报告 VprBP 对 p53 的丝氨酸 367 磷酸化 (S367p) 是减弱 p53 转录和生长抑制活动的关键因素。VprBP 通过与 p53 的 C 末端结构域直接相互作用来催化 p53S367p。从机制上讲，VprBP 介导的 S367p 在促进 p53 蛋白酶体降解后抑制 p53 功能，因为阻断 p53S367p 会增加 p53 蛋白水平，从而增强 p53 反式激活。此外，通过 p53 乙酰化消除 VprBP-p53 相互作用对于防止 p53S367p 和增强 p53 响应 DNA 损伤的功能至关重要。总之，我们的研究结果将 VprBP 介导的 S367p 确定为 p53 功能的负调节因子，并确定了 S367p 调节 p53 稳定性的先前未表征的机制。