Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

Abstract

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.

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Correction for Kim et al., “Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail”

ACKNOWLEDGMENTS

We acknowledge Peter Jones for the Urotsa and LD611 cell lines, Michael Lieber for DNA-PK, Igor Pogribny for the MCF10-2A cell line, Daniela Rhodes for p601-7, Pradip Roy-Burman for the MLC and LNCaP cell lines, Jacek Skowronski for pCG-Myc-VprBP, Michael Kastan for pcDNA3.1-Flag-ATM, and Karlene Cimprich for pBJ5.1-Flag-ATR. We also thank Deborah Johnson and members of the An laboratory for their instructive discussions and valuable suggestions.

This work was supported by NIH grant R01GM84209, ACS Research Scholar grant DMC-1005001, and Department of Defense grant W81XWH0910330, awarded to W.A.