Cyclin A is regulated primarily through transcription control during the mammalian cell cycle. A dual mechanism of cyclin A transcriptional repression involves, on the one hand, promoter-bound inhibitory complexes of E2F transcription factors and RB (retinoblastoma) family proteins, and on the other, chromatin-directed histone deacetylase activity that is recruited to the cyclin A promoter early in the cell cycle in association with these RB proteins. This dual regulation maintains transcriptional silence of the cyclin A locus until its transcription is required in S-phase. At that time, RB family members dissociate from E2F proteins and nucleosomal restructuring of the locus takes place, to permit transcriptional activation and resultant S-phase progression to proceed. We have identified a double bromo-domain-containing protein Brd2, which exhibits apparent ‘scaffold’ or transcriptional adapter functions and mediates recruitment of both E2F transcription factors and chromatin-remodelling activity to the cyclin A promoter. We have shown previously that Brd2-containing nuclear, multiprotein complexes contain E2F-1 and -2. In the present study, we show that, in S-phase, they also contain histone H4-directed acetylase activity. Overexpression of Brd2 in fibroblasts accelerates the cell cycle through increased expression of cyclin A and its associated cyclin-dependent kinase activity. Chromatin immunoprecipitation studies show that Brd2 is physically present at the cyclin A promoter and its overexpression promotes increased histone H4 acetylation at the promoter as it becomes transcriptionally active, suggesting a new model for the dual regulation of cyclin A.
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Research Article|
March 22 2005
Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A1
Anupama SINHA;
Anupama SINHA
1Cancer Research Center, Boston University School of Medicine, 80 East Concord Street, K521, Boston, MA 02118, U.S.A.
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Douglas V. FALLER;
Douglas V. FALLER
1Cancer Research Center, Boston University School of Medicine, 80 East Concord Street, K521, Boston, MA 02118, U.S.A.
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Gerald V. DENIS
Gerald V. DENIS
2
1Cancer Research Center, Boston University School of Medicine, 80 East Concord Street, K521, Boston, MA 02118, U.S.A.
2To whom correspondence should be addressed (email gdenis@bu.edu).
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Publisher: Portland Press Ltd
Received:
October 25 2004
Accepted:
November 17 2004
Accepted Manuscript online:
November 17 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 387 (1): 257–269.
Article history
Received:
October 25 2004
Accepted:
November 17 2004
Accepted Manuscript online:
November 17 2004
Citation
Anupama SINHA, Douglas V. FALLER, Gerald V. DENIS; Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A. Biochem J 1 April 2005; 387 (1): 257–269. doi: https://doi.org/10.1042/BJ20041793
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