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BRD4 (bromodomain containing 4)

Identity

Other namesHUNK1
MCAP
HGNC (Hugo) BRD4
LocusID (NCBI) 23476
Location 19p13.12
Location_base_pair Starts at 15357847 and ends at 15391262 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The gene consists of 20 exons that span approximately 43 kb of genomic DNA in the centromere-to-telomere orientation. The translation initiation codon and stop codon are located to exon 2 and exon 20, respectively.
Transcription Two isoforms of BRD4 have been reported. The "BRD4 long isoform" corresponds to the ordinary full length transcript while the "BRD4 short isoform" corresponds to an alternative splicing variant lacking exons 12-20. The "BRD4 long variant" encodes a 6.0 kb transcript and the "BRD4 short variant" encodes a 4.4 kb transcript.

Protein

Description BRD4 belongs to the BET subgroup of the bromodomain superfamily and contains 2 bromodomains and a conserved ET-domain.
The open reading frame encodes a 1362 amino acid protein with a molecular weight of 200 kDa.
Expression Northen blot analysis has shown an ubiquitous normal expression of both BRD4 isoforms.
Localisation Nuclear.
Function A striking feature of BRD4 is its association with euchromatic regions of mitotic chromosomes. By this association, the protein exerts its function as regulator of cell cycle progression from G2 to M but also in the G1 to S transition. It has also been suggested that the association of BRD4 to chromatin is important for the transmission of a transcriptional memory during cell division.

Implicated in

Entity Carcinoma with t(15;19)(q14;p13) translocation.
Prognosis Carcinoma with t(15;19) translocation is invariably fatal with a rapid clinical course when located to the midline thoracic, head and neck structures. One tumor, displaying the cytogenetic and molecular cytogenetic features of carcinoma with t(15;19) translocation, but located to the iliac bone, has been reported as successfully cured.
Cytogenetics t(15;19)(q14;p13) [reported breakpoints: t(15;19)(q11-15;p13)].
Hybrid/Mutated Gene The t(15;19)(q14;p13) results in a BRD4-NUT chimeric gene where exon 10 of BRD4 is fused to exon 2 of NUT.
Abnormal Protein The BRD4-NUT fusion protein is composed of the N-terminal of BRD4 (amino acids 1-720 out of 1372) and almost the entire protein sequence of NUT (amino acids 6-1127). The N-terminal of BRD4 includes bromodomains 1 and 2 and other, less well characterized functional domains.
Oncogenesis It has been suggested that the oncogenic effect of the NUT-BRD4 fusion is caused not only by the abnormal regulation of NUT by BRD4 promoter elements but also by the consequent ectopic expression of NUT in non-germinal tissues.
  

Breakpoints

Note The vast majority of reported 19p breakpoints were assigned to band 19p13, the exception being the cytogenetic interpretation of a 19q13 breakpoint reported once. The reported breakpoints on chromosome 15 have varied (15q11-q15).

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors ProstateOverviewID5041

External links

Nomenclature
HGNC (Hugo)BRD4   13575
Cards
AtlasBRD4ID837ch19p13
Entrez_Gene (NCBI)BRD4  23476  bromodomain containing 4
GeneCards (Weizmann)BRD4
Ensembl (Hinxton)ENSG00000141867 [Gene_View]  chr19:15357847-15391262 [Contig_View]  BRD4 [Vega]
ICGC DataPortalENSG00000141867
cBioPortalBRD4
AceView (NCBI)BRD4
Genatlas (Paris)BRD4
WikiGenes23476
SOURCE (Princeton)NM_014299 NM_058243
Genomic and cartography
GoldenPath (UCSC)BRD4  -  19p13.12   chr19:15357847-15391262 -  19   [Description]    (hg19-Feb_2009)
EnsemblBRD4 - 19 [CytoView]
Mapping of homologs : NCBIBRD4 [Mapview]
OMIM608749   
Gene and transcription
Genbank (Entrez)AF386649 AK307664 BC000156 BC008354 BC030158
RefSeq transcript (Entrez)NM_014299 NM_058243
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NT_011295 NW_001838484 NW_004929414
Consensus coding sequences : CCDS (NCBI)BRD4
Cluster EST : UnigeneHs.187763 [ NCBI ]
CGAP (NCI)Hs.187763
Alternative Splicing : Fast-db (Paris)GSHG0015581
Alternative Splicing GalleryENSG00000141867
Gene ExpressionBRD4 [ NCBI-GEO ]     BRD4 [ SEEK ]   BRD4 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtO60885 (Uniprot)
NextProtO60885  [Medical]
With graphics : InterProO60885
Splice isoforms : SwissVarO60885 (Swissvar)
Domaine pattern : Prosite (Expaxy)BROMODOMAIN_1 (PS00633)    BROMODOMAIN_2 (PS50014)    NET (PS51525)   
Domains : Interpro (EBI)Bromodomain [organisation]   Bromodomain_CS [organisation]   NET_dom [organisation]  
Related proteins : CluSTrO60885
Domain families : Pfam (Sanger)Bromodomain (PF00439)   
Domain families : Pfam (NCBI)pfam00439   
Domain families : Smart (EMBL)BROMO (SM00297)  
DMDM Disease mutations23476
Blocks (Seattle)O60885
PDB (SRS)2I8N    2LSP    2NNU    2OSS    2OUO    2YEL    2YEM    3MXF    3P5O    3SVF    3SVG    3U5J    3U5K    3U5L    3UVW    3UVX    3UVY    3UW9    3ZYU    4A9L    4DON    4E96    4F3I    4GPJ    4HBV    4HBW    4HBX    4HBY    4HXK    4HXL    4HXM    4HXN    4HXO    4HXP    4HXR    4HXS    4J0R    4J0S    4KV1    4KV4   
PDB (PDBSum)2I8N    2LSP    2NNU    2OSS    2OUO    2YEL    2YEM    3MXF    3P5O    3SVF    3SVG    3U5J    3U5K    3U5L    3UVW    3UVX    3UVY    3UW9    3ZYU    4A9L    4DON    4E96    4F3I    4GPJ    4HBV    4HBW    4HBX    4HBY    4HXK    4HXL    4HXM    4HXN    4HXO    4HXP    4HXR    4HXS    4J0R    4J0S    4KV1    4KV4   
PDB (IMB)2I8N    2LSP    2NNU    2OSS    2OUO    2YEL    2YEM    3MXF    3P5O    3SVF    3SVG    3U5J    3U5K    3U5L    3UVW    3UVX    3UVY    3UW9    3ZYU    4A9L    4DON    4E96    4F3I    4GPJ    4HBV    4HBW    4HBX    4HBY    4HXK    4HXL    4HXM    4HXN    4HXO    4HXP    4HXR    4HXS    4J0R    4J0S    4KV1    4KV4   
PDB (RSDB)2I8N    2LSP    2NNU    2OSS    2OUO    2YEL    2YEM    3MXF    3P5O    3SVF    3SVG    3U5J    3U5K    3U5L    3UVW    3UVX    3UVY    3UW9    3ZYU    4A9L    4DON    4E96    4F3I    4GPJ    4HBV    4HBW    4HBX    4HBY    4HXK    4HXL    4HXM    4HXN    4HXO    4HXP    4HXR    4HXS    4J0R    4J0S    4KV1    4KV4   
Human Protein AtlasENSG00000141867 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasO60885
HPRD10574
IPIIPI00440727   IPI00440728   IPI00477699   
Protein Interaction databases
DIP (DOE-UCLA)O60885
IntAct (EBI)O60885
FunCoupENSG00000141867
BioGRIDBRD4
InParanoidO60885
Interologous Interaction database O60885
IntegromeDBBRD4
STRING (EMBL)BRD4
Ontologies - Pathways
Ontology : AmiGOregulation of transcription involved in G1/S transition of mitotic cell cycle  nuclear chromatin  condensed nuclear chromosome  inner cell mass cell proliferation  p53 binding  DNA binding  chromatin binding  protein binding  nucleus  chromosome  nucleolus  cytoplasm  chromatin remodeling  transcription, DNA-templated  protein phosphorylation  cellular response to DNA damage stimulus  cellular response to DNA damage stimulus  chromosome segregation  positive regulation of G2/M transition of mitotic cell cycle  modulation by virus of host morphology or physiology  positive regulation of transcription elongation from RNA polymerase II promoter  positive regulation of transcription elongation from RNA polymerase II promoter  positive regulation of I-kappaB kinase/NF-kappaB cascade  positive regulation of DNA binding  histone H4-K12 acetylation  histone H3-K14 acetylation  positive regulation of transcription from RNA polymerase II promoter  regulation of inflammatory response  histone acetyl-lysine binding  regulation of phosphorylation of RNA polymerase II C-terminal domain  negative regulation of DNA damage checkpoint  
Ontology : EGO-EBIregulation of transcription involved in G1/S transition of mitotic cell cycle  nuclear chromatin  condensed nuclear chromosome  inner cell mass cell proliferation  p53 binding  DNA binding  chromatin binding  protein binding  nucleus  chromosome  nucleolus  cytoplasm  chromatin remodeling  transcription, DNA-templated  protein phosphorylation  cellular response to DNA damage stimulus  cellular response to DNA damage stimulus  chromosome segregation  positive regulation of G2/M transition of mitotic cell cycle  modulation by virus of host morphology or physiology  positive regulation of transcription elongation from RNA polymerase II promoter  positive regulation of transcription elongation from RNA polymerase II promoter  positive regulation of I-kappaB kinase/NF-kappaB cascade  positive regulation of DNA binding  histone H4-K12 acetylation  histone H3-K14 acetylation  positive regulation of transcription from RNA polymerase II promoter  regulation of inflammatory response  histone acetyl-lysine binding  regulation of phosphorylation of RNA polymerase II C-terminal domain  negative regulation of DNA damage checkpoint  
Protein Interaction DatabaseBRD4
Wikipedia pathwaysBRD4
Gene fusion - rearrangments
Rearrangement : COSMICBRD4 [19p13.12]  -  C15orf55 [780]  
  [COSF781] [COSF821] [COSF972] 
Rearrangement : TICdbNUTM1 [15q14]  -  BRD4 [5q32]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)BRD4
snp3D : Map Gene to Disease23476
SNP (GeneSNP Utah)BRD4
SNP : HGBaseBRD4
Genetic variants : HAPMAPBRD4
Exome VariantBRD4
1000_GenomesBRD4 
ICGC programENSG00000141867 
Cancer Gene: CensusBRD4 
Somatic Mutations in Cancer : COSMICBRD4 
CONAN: Copy Number AnalysisBRD4 
Mutations and Diseases : HGMDBRD4
Genomic VariantsBRD4  BRD4 [DGVbeta]
dbVarBRD4
ClinVarBRD4
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM608749   
MedgenBRD4
GENETestsBRD4
Disease Genetic AssociationBRD4
Huge Navigator BRD4 [HugePedia]  BRD4 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneBRD4
Homology/Alignments : Family Browser (UCSC)BRD4
Phylogenetic Trees/Animal Genes : TreeFamBRD4
Chemical/Protein Interactions : CTD23476
Chemical/Pharm GKB GenePA25416
Clinical trialBRD4
Cancer Resource (Charite)ENSG00000141867
Other databases
Probes
Litterature
PubMed80 Pubmed reference(s) in Entrez
CoreMineBRD4
iHOPBRD4

Bibliography

Intrathoracic carcinoma in an 11-year-old girl showing a translocation t(15;19).
Kees UR, Mulcahy MT, Willoughby ML
The American journal of pediatric hematology/oncology. 1991 ; 13 (4) : 459-464.
PMID 1785673
 
A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition.
Dey A, Ellenberg J, Farina A, Coleman AE, Maruyama T, Sciortino S, Lippincott-Schwartz J, Ozato K
Molecular and cellular biology. 2000 ; 20 (17) : 6537-6549.
PMID 10938129
 
You bet-cha: a novel family of transcriptional regulators.
Florence B, Faller DV
Frontiers in bioscience : a journal and virtual library. 2001 ; 6 : D1008-D1018.
PMID 11487468
 
BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19).
French CA, Miyoshi I, Aster JC, Kubonishi I, Kroll TG, Dal Cin P, Vargas SO, Perez-Atayde AR, Fletcher JA
The American journal of pathology. 2001 ; 159 (6) : 1987-1992.
PMID 11733348
 
A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase.
Maruyama T, Farina A, Dey A, Cheong J, Bermudez VP, Tamura T, Sciortino S, Shuman J, Hurwitz J, Ozato K
Molecular and cellular biology. 2002 ; 22 (18) : 6509-6520.
PMID 12192049
 
The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis.
Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K
Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (15) : 8758-8763.
PMID 12840145
 
BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma.
French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA
Cancer research. 2003 ; 63 (2) : 304-307.
PMID 12543779
 
Midline carcinoma of children and young adults with NUT rearrangement.
French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, Nose V, Vargas SO, Moschovi M, Tzortzatou-Stathopoulou F, Miyoshi I, Perez-Atayde AR, Aster JC, Fletcher JA
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004 ; 22 (20) : 4135-4139.
PMID 15483023
 
Carcinoma with t(15;19) translocation.
Marx A, French CA, Fletcher JA
In..
 
Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes.
You J, Croyle JL, Nishimura A, Ozato K, Howley PM
Cell. 2004 ; 117 (3) : 349-360.
PMID 15109495
 
Midline carcinoma with t(15;19) and BRD4-NUT fusion oncogene in a 30-year-old female with response to docetaxel and radiotherapy.
Engleson J, Soller M, Panagopoulos I, Dahlą©n A, Dictor M, Jerkeman M
BMC cancer. 2006 ; 6 : page 69.
PMID 16542442
 
Successful treatment of a child with t(15;19)-positive tumor.
Mertens F, Wiebe T, Adlercreutz C, Mandahl N, French CA
Pediatric blood & cancer. 2007 ; 49 (7) : 1015-1017.
PMID 16435379
 
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Contributor(s)

Written02-2007Anna Collin

Citation

This paper should be referenced as such :
Collin, A
BRD4 (bromodomain containing 4)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):180-181.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/BRD4ID837ch19p13.html

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indexed on : Fri Jul 11 17:03:06 CEST 2014

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