Bromodomain-containing protein 3

Bromodomain containing 3

PDB rendering based on 2nxb.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BRD3 ; ORFX; RING3L
External IDs OMIM: 601541 MGI: 1914632 HomoloGene: 81801 ChEMBL: 1795186 GeneCards: BRD3 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 8019 67382
Ensembl ENSG00000169925 ENSMUSG00000026918
UniProt Q15059 Q8K2F0
RefSeq (mRNA) NM_007371 NM_001113573
RefSeq (protein) NP_031397 NP_001107045
Location (UCSC) Chr 9:
134.03 – 134.07 Mb		 Chr 2:
27.45 – 27.51 Mb
PubMed search

Bromodomain-containing protein 3 (BRD3) also known as RING3-like protein (RING3L) is a protein that in humans is encoded by the BRD3 gene.[1][2][3] This gene was identified based on its homology to the gene encoding the RING3 (BRD2) protein, a serine/threonine kinase. The gene localizes to 9q34, a region which contains several major histocompatibility complex (MHC) genes.

Structure

BRD3 is a member of the Bromodomain and Extra-Terminal motif (BET) protein family. Like other BET family members it contains two tandem homologous bromodomains and an "Extra-Terminal" motif.

BRD3, similar to BRD2, does not have a long C-terminal domain as BET family proteins BRD4 and BRDT do.[4]

Function

BRD3 is a member of the BET (Bromodomain and Extra-Terminal motif) protein family. Like other BET protein family members, BRD3 associates with acetylated lysine residues on histones and transcription factors.[5][6]

BRD3 has been implicated in nucleosome remodeling in the context of transcription.[7]

BRD2 and BRD3 perform overlapping cellular functions.[8]

Clinical significance

Chromosomal translocation of BRD3 with the NUT gene has been implicated in NUT midline carcinoma.[9] BRD3-NUT driven cancers are histopathologically indistiguishable from BRD4-NUT driven cancers, likely because these translocations involve the N-terminal portion bromodomain-containing portion of these proteins which are highly conserved.

Depletion of BRD3 slows growth in cancer models including prostate cancer and medulloblastoma. The effect of BRD3 depletion is milder than that of other BET proteins BRD2 and BRD4 when each is tested in isolation.[10][11] BET inhibitors target highly conserved BET bromodomains and displace BRD2, BRD3, and BRD4 from chromatin simultaneously. Functional redundancy between BRD2 and BRD3 suggests that their simultaneous disruption of these proteins may be more important than is appreciated by depletion of these proteins individually.[12]

References

  1. ↑ Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S (Dec 1995). "Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1". DNA Research 1 (5): 223–9. doi:10.1093/dnares/1.5.223. PMID 7584044.
  2. ↑ Thorpe KL, Abdulla S, Kaufman J, Trowsdale J, Beck S (Oct 1996). "Phylogeny and structure of the RING3 gene". Immunogenetics 44 (5): 391–6. doi:10.1007/BF02602785. PMID 8781126.
  3. ↑ "Entrez Gene: BRD3 bromodomain containing 3".
  4. ↑ Belkina AC, Denis GV (Jul 2012). "BET domain co-regulators in obesity, inflammation and cancer". Nature Reviews. Cancer 12 (7): 465–77. doi:10.1038/nrc3256. PMC 3934568. PMID 22722403.
  5. ↑ Gamsjaeger R, Webb SR, Lamonica JM, Billin A, Blobel GA, Mackay JP (Jul 2011). "Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3". Molecular and Cellular Biology 31 (13): 2632–40. doi:10.1128/MCB.05413-11. PMID 21555453.
  6. ↑ Lamonica JM, Deng W, Kadauke S, Campbell AE, Gamsjaeger R, Wang H, Cheng Y, Billin AN, Hardison RC, Mackay JP, Blobel GA (May 2011). "Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes". Proceedings of the National Academy of Sciences of the United States of America 108 (22): E159–68. doi:10.1073/pnas.1102140108. PMC 3107332. PMID 21536911.
  7. ↑ LeRoy G, Rickards B, Flint SJ (Apr 2008). "The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription". Molecular Cell 30 (1): 51–60. doi:10.1016/j.molcel.2008.01.018. PMC 2387119. PMID 18406326.
  8. ↑ Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA (Feb 2015). "Functions of BET proteins in erythroid gene expression". Blood 125: 2825–34. doi:10.1182/blood-2014-10-607309. PMID 25696920.
  9. ↑ French CA (2012). "Pathogenesis of NUT midline carcinoma". Annual Review of Pathology 7: 247–65. doi:10.1146/annurev-pathol-011811-132438. PMID 22017582.
  10. ↑ Asangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, Escara-Wilke J, Wilder-Romans K, Dhanireddy S, Engelke C, Iyer MK, Jing X, Wu YM, Cao X, Qin ZS, Wang S, Feng FY, Chinnaiyan AM (Jun 2014). "Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer". Nature 510 (7504): 278–82. doi:10.1038/nature13229. PMC 4075966. PMID 24759320.
  11. ↑ Tang Y, Gholamin S, Schubert S, Willardson MI, Lee A, Bandopadhayay P, Bergthold G, Masoud S, Nguyen B, Vue N, Balansay B, Yu F, Oh S, Woo P, Chen S, Ponnuswami A, Monje M, Atwood SX, Whitson RJ, Mitra S, Cheshier SH, Qi J, Beroukhim R, Tang JY, Wechsler-Reya R, Oro AE, Link BA, Bradner JE, Cho YJ (Jul 2014). "Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition". Nature Medicine 20 (7): 732–40. doi:10.1038/nm.3613. PMC 4108909. PMID 24973920.
  12. ↑ Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA (Apr 2015). "Functions of BET proteins in erythroid gene expression". Blood 125 (18): 2825–34. doi:10.1182/blood-2014-10-607309. PMID 25696920.

Further reading

  • Thorpe KL, Gorman P, Thomas C, Sheer D, Trowsdale J, Beck S (Oct 1997). "Chromosomal localization, gene structure and transcription pattern of the ORFX gene, a homologue of the MHC-linked RING3 gene". Gene 200 (1-2): 177–83. doi:10.1016/S0378-1119(97)00415-0. PMID 9373153. 
  • Kaneko H, Inoue R, Teramoto T, Morimoto W, Isogai K, Kasahara K, Kondo N (2003). "Detection of the genes induced in activated lymphocytes by modified differential display". Journal of Investigational Allergology & Clinical Immunology 12 (2): 86–90. PMID 12371535. 
  • Zhou M, Peng C, Nie XM, Zhang BC, Zhu SG, Yu Y, Li XL, Li GY (Feb 2003). "[Expression of BRD7-interacting proteins,BRD2 and BRD3, in nasopharyngeal carcinoma tissues]". Ai Zheng = Aizheng = Chinese Journal of Cancer 22 (2): 123–7. PMID 12600283. 
  • Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (Aug 2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proceedings of the National Academy of Sciences of the United States of America 101 (33): 12130–5. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935. 
  • Ishii H, Mimori K, Mori M, Vecchione A (Jul 2005). "Differentially expressed genes in endothelial differentiation". DNA and Cell Biology 24 (7): 432–7. doi:10.1089/dna.2005.24.432. PMID 16008511. 
  • Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (Nov 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983. 


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