Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail
Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail
复制标题
DOI：
10.1128/mcb.06037-11
复制
发表时间：
2012-02-01
影响因子：
5.3
通讯作者：
An, Woojin
中科院分区：
文献类型：
--
作者：
Kim, Kyunghwan;Heo, Kyu;An, Woojin
HIV-1 Vpr结合蛋白（VprBP）参与DNA复制和细胞周期进程的调控，但其确切作用尚不清楚。在这里，我们报告，VprBP调节p53诱导的转录和凋亡途径。VprBP被募集到p53应答启动子，并在没有应激刺激的情况下抑制p53的反式激活。为了维持靶启动子处于失活状态，VprBP通过识别未乙酰化的H3尾稳定地结合核小体。H3尾的启动子定位的脱乙酰化是VprBP拴系并作为p53靶基因的真正抑制剂的先决条件。VprBP敲低导致p53靶基因的激活，并导致DNA损伤诱导的细胞凋亡增加。此外，VprBP在丝氨酸895处的磷酸化损害了VprBP结合H3尾和抑制p53反式激活的能力。因此，我们的研究结果揭示了VprBP在调节p53信号通路中的新作用，以及与VprBP失调相关的癌症发展的分子机制。
HIV-1 Vpr-binding protein (VprBP) has been implicated in the regulation of both DNA replication and cell cycle progression, but its precise role remains unclear. Here we report that VprBP regulates the p53-induced transcription and apoptotic pathway. VprBP is recruited to p53-responsive promoters and suppresses p53 transactivation in the absence of stress stimuli. To maintain target promoters in an inactive state, VprBP stably binds to nucleosomes by recognizing unacetylated H3 tails. Promoter-localized deacetylation of H3 tails is a prerequisite for VprBP to tether and act as a bona fide inhibitor at p53 target genes. VprBP knockdown leads to activation of p53 target genes and causes an increase in DNA damage-induced apoptosis. Moreover, phosphorylation of VprBP at serine 895 impairs the ability of VprBP to bind H3 tails and to repress p53 transactivation. Our results thus reveal a new role for VprBP in regulation of the p53 signaling pathway, as well as molecular mechanisms of cancer development related to VprBP misregulation.