The Double Bromodomain-containing Chromatin Adaptor Brd4 and Transcriptional Regulation*

By Shwu-Yuan Wu, C. Chiang. Journal of Biological Chemistry, 2007

642 citations recorded by the source corpus.

Brd4 is a double bromodomain-containing protein that binds preferentially to acetylated chromatin. It belongs to the BET (bromodomains and extraterminal) family that includes mammalian Brd2, Brd3, Brd4, Brdt, Drosophila Fsh, yeast Bdf1, Bdf2, and corresponding homologues in other species. Brd4 is essential for cellular growth and has been implicated in cell cycle control, DNA replication, and gene rearrangement found in t(15;19)-associated carcinomas. Recently, Brd4 has been found in several transcription complexes, including the general cofactor Mediator and the P-TEFb elongation factor, and is capable of stimulating HIV-1 transcription in a Tat-independent manner. In addition, Brd4 is used as a cellular adaptor by some animal and human papillomaviruses (HPV) for anchoring viral genomes to mitotic chromosomes. This tethering, mediated by Brd4 interaction with virus-encoded E2 protein, facilitates viral genome segregation during mitosis. Interestingly, Brd4 is also identified in a transcriptional silencing complex assembled by HPV E2 and turns out to be the long sought cellular corepressor that inhibits the expression of HPV-encoded E6 and E7 oncoproteins that antagonize p53 and pRB tumor suppressor activity, respectively. The dual role of Brd4 in gene activation and repression illustrates how a dynamic chromatin-binding adaptor is able to recruit distinct transcriptional regulators to modulate promoter activity through cell cycle progression.

Subfields: Molecular Biology, Plant Science

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Citations in the corpus

The mechanisms behind the therapeutic activity of BET bromodomain inhibition (2014, background): “Nonetheless, the interaction with Mediator suggests that Brd4 could provide an interface between TFs and the transcriptional apparatus (Wu and Chiang, 2007).”
BRD4 and Cancer: going beyond transcriptional regulation (2018, background): “This function largely but not entirely relies on BRD4 BDs and on their ability to recognize acetyl-proteins [2, 6, 24].”
RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia (2011, background): “Brd4 is a member of the BET family of bromodomain-containing proteins that bind to acetylated histones to influence transcriptio”
Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers (2013, background): “Inhibition of BRD4 Leads to Displacement of BRD4 Genome Wide BRD4 interacts with chromatin-associated proteins such as transcription factors, the Mediator complex, and acetylated histones (Dawson et al., 2011; Dey et al., 2003; Jang et al., 2005; Jiang et al., 1998; Wu and Chiang, 2007; Wu et al., 2”
Targeting MYC dependence in cancer by inhibiting BET bromodomains (2011, background): “BRD2 | BRD3 | BRD4 | JQ1 T BET protein family employs tandem bromodomains to recognize specific acetylated lysine residues in the N-terminal tails of histone proteins (1).”