Bromodomain-containing protein 4
Also known as: BRD4, HUNK1
Function
Chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. Remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure. During interphase, plays a key role in regulating the transcription of signal-inducible genes by associating with the P-TEFb complex and recruiting it to promoters. Also recruits P-TEFb complex to distal enhancers, so called anti-pause enhancers in collaboration with JMJD6. BRD4 and JMJD6 are required to form the transcriptionally active P-TEFb complex by displacing negative regulators such as HEXIM1 and 7SKsnRNA complex from P-TEFb, thereby transforming it into an active form that can then phosphorylate the C-terminal domain (CTD) of RNA polymerase II. Regulates differentiation of naive CD4(+) T-cells into T-helper Th17 by promoting recruitment of P-TEFb to promoters (By similarity). Promotes phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II. According to a report, directly acts as an atypical protein kinase and mediates phosphorylation of 'Ser-2' of the C-terminal domain (CTD) of RNA polymerase II; these data however need additional evidences in vivo. In addition to acetylated histones, also recognizes and binds acetylated RELA, leading to further recruitment of the P-TEFb complex and subsequent activation of NF-kappa-B. Also acts as a regulator of p53/TP53-mediated transcription: following phosphorylation by CK2, recruited to p53/TP53 specific target promoters.
Classification
- Family (Pfam)
- PF17035 BET, PF17105 BRD4_CDT, PF00439 Bromodomain
- InterPro
- BRD4_CDT, Bromo_Brdt_I, Bromo_Brdt_II, Bromo_chromatin_reader, Bromodomain, Bromodomain-like_sf, Bromodomain_CS, NET_dom, NET_sf
- Functional cluster
- RNA-Polymerase II Transcription Factors
Experimental structures · PDB · 602
- 2I8N NMR
- 2LSP NMR
- 2MJV NMR
- 2N3K NMR
- 2NCZ NMR
- 2ND0 NMR
- 2ND1 NMR
- 2NNU X-ray 1.59A
- 2OSS X-ray 1.35A
- 2OUO X-ray 1.89A
- 2YEL X-ray 1.65A
- 2YEM X-ray 2.30A
- … and 590 more
A predicted model is available from AlphaFold.
Gene Ontology · 36
- GO:0000785 chromatin
- GO:0005694 chromosome
- GO:0000794 condensed nuclear chromosome
- GO:0005654 nucleoplasm
- GO:0005634 nucleus
- GO:0003682 chromatin binding
- GO:0019899 enzyme binding
- GO:0042393 histone binding
- GO:0140119 histone H3K27ac reader activity
- GO:0140072 histone H3K9ac reader activity
- GO:0140008 histone H4 reader activity
- GO:0140011 histone H4K12ac reader activity
- GO:0140046 histone H4K16ac reader activity
- GO:0140012 histone H4K5ac reader activity
- GO:0140055 histone H4K8ac reader activity
- GO:0106140 P-TEFb complex binding
- GO:0002039 p53 binding
- GO:0004674 protein serine/threonine kinase activity
- GO:0099122 RNA polymerase II C-terminal domain binding
- GO:0008353 RNA polymerase II CTD heptapeptide repeat kinase activity
- GO:0000976 transcription cis-regulatory region binding
- GO:0003713 transcription coactivator activity
- GO:0003712 transcription coregulator activity
- GO:0006338 chromatin remodeling
- GO:0006974 DNA damage response
- GO:0006351 DNA-templated transcription
- GO:0043922 host-mediated suppression of viral transcription
- GO:2000002 negative regulation of DNA damage checkpoint
- GO:0043123 positive regulation of canonical NF-kappaB signal transduction
- GO:0045893 positive regulation of DNA-templated transcription
- GO:0010971 positive regulation of G2/M transition of mitotic cell cycle
- GO:2000330 positive regulation of T-helper 17 cell lineage commitment
- GO:0045944 positive regulation of transcription by RNA polymerase II
- GO:0032968 positive regulation of transcription elongation by RNA polymerase II
- GO:0050727 regulation of inflammatory response
- GO:0006357 regulation of transcription by RNA polymerase II
Disease associations
- Cornelia de Lange syndrome 6 MONDO:0957921
Drugs targeting this protein · 6
- MOLIBRESIB inhibitor
- APABETALONE inhibitor
- BIRABRESIB inhibitor
- RO-6870810 inhibitor
- EZOBRESIB inhibitor
- PELABRESIB inhibitor
Related proteins · sequence + function similarity
- Bromodomain-containing protein 4 1.00
- Bromodomain-containing protein 4B 0.96
- Bromodomain-containing protein 4A 0.95
- Bromodomain-containing protein 4 0.92
- Bromodomain-containing protein 3 0.84
- Bromodomain-containing protein 3 0.82
- SR-related and CTD-associated factor 4 0.77
- SR-related and CTD-associated factor 4 0.76
- SR-related and CTD-associated factor 4 0.75
- Lysine-specific demethylase 9 0.75
- Synaptic defective enhancer 1 0.75
- Bromodomain-containing protein 2 0.74
Co-cited proteins · studied together in the literature
- Bromodomain-containing protein 4 5 shared papers
- Bromodomain-containing protein 2 3 shared papers
- NUT family member 1 1 shared papers
- Nipped-B-like protein 3 shared papers
- Bromodomain-containing protein 3 4 shared papers
- Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 3 shared papers
- Histone-lysine N-methyltransferase NSD3 2 shared papers
- Regulatory protein E2 1 shared papers
- Cyclin-T1 3 shared papers
- Condensin-2 complex subunit D3 1 shared papers
- Structural maintenance of chromosomes protein 2 1 shared papers
- Cyclin-dependent kinase 9 3 shared papers
Literature · 56 cited papers
- Understanding the new BRD4-related syndrome: Clinical and genomic delineation with an international cohort study. Clin. Genet. · 2022
- Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation. Science · 2020
- Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer. Nature · 2020
- PMID 31168063 Nat. Genet. · 2019
- PMID 29440723 Nat. Genet. · 2018
- BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome. Nat. Genet. · 2018
- Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes. J. Biol. Chem. · 2018
- Structural Mechanism of the Oxygenase JMJD6 Recognition by the Extraterminal (ET) Domain of BRD4. Sci. Rep. · 2017
- Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
- SUMO-2 orchestrates chromatin modifiers in response to DNA damage. Cell Rep. · 2015
- System-wide analysis of SUMOylation dynamics in response to replication stress reveals novel small ubiquitin-like modified target proteins and acceptor lysines relevant for genome stability. Mol. Cell. Proteomics · 2015
- Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination. Genes Dev. · 2015
- … and 44 more in the literature graph