Brd4 links chromatin targeting to HPV transcriptional silencing Journal Article

Authors: Wu, S. Y.; Lee, A. Y.; Hou, S. Y.; Kemper, J. K.; Erdjument-Bromage, H.; Tempst, P.; Chiang, C. M.
Article Title: Brd4 links chromatin targeting to HPV transcriptional silencing
Abstract: The E2 protein encoded by human papillomaviruses (HPVs) inhibits expression of the viral E6 oncoprotein, which, in turn, regulates p53 target gene transcription. To identify cellular proteins involved in E2-mediated transcriptional repression, we isolated an E2 complex from human cells conditionally expressing HPV-11 E2. Surprisingly, the double bromodomain-containing protein Brd4, which is implicated in cell cycle control and viral genome segregation, was found associated with E2 and conferred on E2 the ability to inhibit AP-1-dependent HPV chromatin transcription in an E2-binding site-specific manner as illustrated by in vitro reconstituted chromatin transcription experiments. Knockdown of Brd4 in human cells alleviates E2-mediated repression of HPV transcription. The E2-interacting domain at the extreme C terminus and the chromatin targeting activity of a bromodomain-containing region are both essential for the corepressor activity of Brd4. Interestingly, E2-Brd4 blocks the recruitment of TFIID and RNA polymerase II to the HPV E6 promoter region without inhibiting acetylation of nucleosomal histones H3 and H4, indicating an acetylation-dependent role of Brd4 in the recruitment of E2 for transcriptional silencing of HPV gene activity. Our finding that Brd4 is a component of the virus-assembled transcriptional silencing complex uncovers a novel function of Brd4 as a cellular cofactor modulating viral gene expression. © 2006 by Cold Spring Harbor Laboratory Press.
Keywords: protein expression; unclassified drug; oncoprotein; human cell; promoter region; protein domain; animals; mice; gene targeting; reverse transcription polymerase chain reaction; carboxy terminal sequence; protein assembly; cell protein; transcription, genetic; in vitro study; hela cells; chromatin; histone h3; recombinant protein; oncogene proteins, fusion; binding site; gene silencing; cell cycle regulation; rna polymerase ii; acetylation; wart virus; gene activity; protein isolation; viral proteins; nucleosome; gene expression regulation, viral; histone h4; human papillomavirus; virus gene; transcription factor ap 1; human papillomavirus 18; hpv; papillomaviridae; gene segregation; human papillomavirus 11; ap-1; e2; brd4; chromatin transcription; protein brd4; transcription factor iid; human papillomavirus type 11; virus transcription
Journal Title: Genes and Development
Volume: 20
Issue: 17
ISSN: 0890-9369
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2006-09-01
Start Page: 2383
End Page: 2396
Language: English
DOI: 10.1101/gad.1448206
PUBMED: 16921027
PROVIDER: scopus
PMCID: PMC1560413
Notes: --- - "Cited By (since 1996): 58" - "Export Date: 4 June 2012" - "CODEN: GEDEE" - "Source: Scopus"
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MSK Authors
  1. Paul J Tempst
    315 Tempst