Bromodomain-containing protein 3 explained

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 maps 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

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] In addition, BRD3 has been shown to interact with RNA molecules and form protein-RNA aggregates.^[8]

BRD2 and BRD3 perform overlapping cellular functions.^[9]

Clinical significance

Chromosomal translocation of BRD3 with the NUT gene has been implicated in NUT midline carcinoma.^[10] BRD3-NUT driven cancers are histopathologically indistinguishable 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.^{[11] [12]} 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.^[13]

Further reading

• Thorpe KL, Gorman P, Thomas C, Sheer D, Trowsdale J, Beck S . 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 . Oct 1997 . 9373153 . 10.1016/S0378-1119(97)00415-0 .
• Kaneko H, Inoue R, Teramoto T, Morimoto W, Isogai K, Kasahara K, Kondo N . Detection of the genes induced in activated lymphocytes by modified differential display . Journal of Investigational Allergology & Clinical Immunology . 12 . 2 . 86–90 . 2003 . 12371535 .
• Zhou M, Peng C, Nie XM, Zhang BC, Zhu SG, Yu Y, Li XL, Li GY . [Expression of BRD7-interacting proteins,BRD2 and BRD3, in nasopharyngeal carcinoma tissues] . AI Zheng = Aizheng = Chinese Journal of Cancer . 22 . 2 . 123–7 . Feb 2003 . 12600283 .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . 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 . Aug 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Ishii H, Mimori K, Mori M, Vecchione A . Differentially expressed genes in endothelial differentiation . DNA and Cell Biology . 24 . 7 . 432–7 . Jul 2005 . 16008511 . 10.1089/dna.2005.24.432 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . Nov 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .

Notes and References

1. Nomura N, Nagase T, Miyajima N, Sazuka T, Tanaka A, Sato S, Seki N, Kawarabayasi Y, Ishikawa K, Tabata S . 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 . Dec 1995 . 7584044 . 10.1093/dnares/1.5.223 . free .
2. Thorpe KL, Abdulla S, Kaufman J, Trowsdale J, Beck S . Phylogeny and structure of the RING3 gene . Immunogenetics . 44 . 5 . 391–6 . Oct 1996 . 8781126 . 10.1007/BF02602785 . 44613743 .
3. Web site: Entrez Gene: BRD3 bromodomain containing 3.
4. Belkina AC, Denis GV . BET domain co-regulators in obesity, inflammation and cancer . Nature Reviews. Cancer . 12 . 7 . 465–77 . Jul 2012 . 22722403 . 3934568 . 10.1038/nrc3256 .
5. Gamsjaeger R, Webb SR, Lamonica JM, Billin A, Blobel GA, Mackay JP . Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3 . Molecular and Cellular Biology . 31 . 13 . 2632–40 . Jul 2011 . 21555453 . 10.1128/MCB.05413-11 . 3133386.
6. Lamonica JM, Deng W, Kadauke S, Campbell AE, Gamsjaeger R, Wang H, Cheng Y, Billin AN, Hardison RC, Mackay JP, Blobel GA . 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 . May 2011 . 21536911 . 10.1073/pnas.1102140108 . 3107332. free .
7. LeRoy G, Rickards B, Flint SJ . The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription . Molecular Cell . 30 . 1 . 51–60 . Apr 2008 . 18406326 . 2387119 . 10.1016/j.molcel.2008.01.018 .
8. Daneshvar K, Ardehali MB, Klein IA, Hsieh FK, Kratkiewicz AJ, Mahpour A . etal. lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation. . Nat Cell Biol . 2020 . 22 . 10 . 1211–1222 . 32895492 . 10.1038/s41556-020-0572-2 . 8008247 .
9. Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA . Functions of BET proteins in erythroid gene expression . Blood . Feb 2015 . 25696920 . 10.1182/blood-2014-10-607309 . 125 . 18 . 2825–34 . 4424630.
10. French CA . Pathogenesis of NUT midline carcinoma . Annual Review of Pathology . 7 . 22017582 . 10.1146/annurev-pathol-011811-132438 . 2012 . 247–65.
11. 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 . Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer . Nature . 510 . 7504 . 278–82 . Jun 2014 . 24759320 . 4075966 . 10.1038/nature13229 . 2014Natur.510..278A .
12. 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 . Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition . Nature Medicine . 20 . 7 . 732–40 . Jul 2014 . 24973920 . 4108909 . 10.1038/nm.3613 .
13. Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA . Functions of BET proteins in erythroid gene expression . Blood . 125 . 18 . Apr 2015 . 25696920 . 10.1182/blood-2014-10-607309 . 2825–34 . 4424630.