Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail Kyunghwan Kim a , Kyu Heo a , b , Jongkyu Choi a , Sarah Jackson c , Hyunjung Kim a , Yue Xiong c and Woojin An a a Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA b Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, South Korea c Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA 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.
Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail
Abstract
Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail Kyunghwan Kim a , Kyu Heo a , b , Jongkyu Choi a , Sarah Jackson c , Hyunjung Kim a , Yue Xiong c and Woojin An a a Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California, USA b Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, South Korea c Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA 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.Preview Only. This article cannot be rented because we do not currently have permission from the publisher.
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Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail
Kim, Kyunghwan; Heo, Kyu; Choi, Jongkyu; Jackson, Sarah; Kim, Hyunjung; Xiong, Yue; An, Woojin
Follow Molecular and Cellular Biology
, Volume 32 (4): 783
American Society For Microbiology – Feb 15, 2012
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