Mechanisms of transcription repression by HIV‐1 Vpr binding protein

Abstract

In the human body, genomic DNA is compacted into each cell's nucleus as a highly‐organized structure called chromatin. Histones are the major protein components to establish this extensive packaging of DNA within the limited volume of the nucleus. Regulation of transcription processes within this chromatin context requires histone modifying activities that counterbalance this repressive nature of chromatin. HIV‐1 Vpr binding protein (VprBP) was originally identified on the basis of its ability to interact with HIV‐1 Vpr protein and implicated in DNA replication and cell cycle regulation, but its precise role remains unclear. Here, we show that VprBP suppresses p53 transactivation by recognizing unmodified histone H3tail via its Lis homology domain. RNAi‐complemented ChIP and binding assays demonstrate that HDAC1‐mediated deacetylation of H3 tail is prerequisite to tether VprBP at p53 target gene promoters. Furthermore, suppression of VprBP expression induces transcription of p53 target genes, and causes an increase in DNA damage‐induced cell death. Consistent with these results, VprBP is over‐expressed in human cancer cells, and this increased level of VprBP is tightly correlated with reduced apoptosis. Our results thus reveal a previously unknown role for VprBP in DNA repair pathway and illustrate the power of combined biochemical and cellular approaches for mechanistic analyses.