title: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
authors.forename: Kyunghwan
authors.initials: K
authors.lastname: Kim
authors.forename: Kyu
authors.initials: K
authors.lastname: Heo
authors.forename: Jongkyu
authors.initials: J
authors.lastname: Choi
authors.forename: Sarah
authors.initials: S
authors.lastname: Jackson
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Kim
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.forename: Woojin
authors.initials: W
authors.lastname: An
mesh_terms: D000107:Acetylation; D017209:Apoptosis; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D006657:Histones; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D044767:Ubiquitin-Protein Ligases; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases