Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
Mol Cell Biol. 2012 Feb;32(4):783-96. doi: 10.1128/MCB.06037-11. Epub 2011 Dec 19.
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.
HIV-1 Vpr 结合蛋白（VprBP）已被牵涉到 DNA 复制和细胞周期进程的调控中，但它的确切作用仍不清楚。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 反应性启动子上，并在没有应激刺激的情况下抑制 p53 反式激活。为了使靶启动子保持非活性状态，VprBP 通过识别未乙酰化的 H3 尾巴稳定地结合到核小体上。H3 尾巴的启动子定位去乙酰化是 VprBP 连接并作为 p53 靶基因的真正抑制剂的前提条件。VprBP 的敲低导致 p53 靶基因的激活，并导致 DNA 损伤诱导的凋亡增加。此外，VprBP 在丝氨酸 895 处的磷酸化会损害 VprBP 结合 H3 尾巴和抑制 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。
