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.