| Written | 2015-08 | Michael T. Werner, Sarah C. Hsu,, Gerd A. Blobel |
| Division of Hematology, Childrens Hospital of Philadelphia, Philadelphia, PA, United States (MTW, SCH, GAB); Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States (MTW, SCH); blobel@email.chop.edu |
| Abstract | BRD3 is a ubiquitously expressed member of the bromodomain and extraterminal motif (BET) family of proteins that use their tandem N-terminal bromodomains to associate with acetylated histones and transcription factors. Translocations involving BRD3 and NUT generate oncogenic fusion proteins that drive NUT midline carcinoma (NMC), an aggressive squamous cell malignancy. In addition, small molecule inhibitors that target the bromodomain-acetyl lysine interaction of all BET proteins are in clinical development for both hematologic malignancies and diverse solid tumors. |
| Keywords | BRD3, ORFX, RING3L, bromodomain-containing protein 3, RING3-like protein, BRD3-NUT, NUT midline carcinoma |
| Identity |
| Alias (NCBI) | ORFX | RING3L |
| HGNC (Hugo) | BRD3 |
| HGNC Alias symb | RING3L | ORFX | KIAA0043 |
| HGNC Alias name | RING3-like |
| HGNC Previous name | bromodomain-containing 3 |
| LocusID (NCBI) | 8019 |
| Atlas_Id | 43171 |
| Location | 9q34.2 [Link to chromosome band 9q34] |
| Location_base_pair | Starts at 134030324 and ends at 134068026 bp from pter ( according to hg19-Feb_2009) [Mapping BRD3.png] |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| BRD3 (9q34.2) / NUTM1 (15q14) | NUTM1 (15q14) / BRD3 (9q34.2) |
| DNA/RNA |
 | |
| Description | BRD3 maps to chromosome 9 on the reverse strand and spans 37.7kb. The gene consists of 12 exons, with the translation initiation codon present in exon 2 and the stop codon in exon 12. BRD3 exhibits a high degree of homology to BRD2, which sits in the MHC locus. In addition to BRD3, chr9q34 contains other MHC-homologous genes, suggesting that BRD2 and BRD3 may have arisen through a gene duplication event (Kasahara et al., 1996; Thorpe et al., 1997). |
| Transcription | BRD3 mRNA (NM_007371.3) is 5,673 base pairs in length. It is expressed across at least fifty adult and fetal tissues (Thorpe et al., 1997). BRD3 has an expression pattern that is similar to BRD2, although the expression levels vary between cell and tissue type. It is not known how BRD3 expression is regulated. An alternatively spliced transcript with a predicted structure missing the C-terminal 170 amino acids has been reported, however there is no experimental validation of this shorter isoform (UniProtKB Q15059-2). |
| Protein |
| Description | BRD3 is a member of the bromodomain and extraterminal motif (BET) family of proteins that includes BRD2, BRD4 and BRDT. BET family members, including BRD3, possess conserved tandem amino-terminal bromodomains that bind to acetylated lysine residues on histones and other proteins. The conserved extraterminal (ET) motif facilitates interactions with several transcriptional regulatory complexes (Rahman et al., 2011), and may be important for the association of BRD3 with viral proteins such as Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA-1) (Ottinger et al., 2006). BRD3 contains two additional domains conserved in other BET family members, motif A and motif B (Paillisson et al., 2007). It has been reported that motif B is important for homo- and heterodimerization of BET proteins, as well as their association with mitotic chromosomes (Garcia-Gutierrez et al., 2012). The function of motif A is unknown. |
| Expression | Based on antibody staining, BRD3 is ubiquitously expressed in most tissues, including in cell lines generated from normal and malignant myeloid and lymphoid cells and non-hematopoietic tumors. Most primary tissues demonstrate significant expression, with the exception of lymphoid tissues, which were observed to have lower relative levels (Uhlen et al., 2015). |
| Localisation | BRD3 is a predominantly nuclear protein (Uhlen et al., 2015) that binds to chromatin (LeRoy et al., 2008; Lamonica et al., 2011; Stonestrom et al., 2015). Like other members of the BET family, BRD3 localizes to mitotic chromosomes (Garcia-Gutierrez et al., 2012) although the functional significance of this has not been determined. In a murine erythroid cell line BRD3 was found to exhibit strong colocalization with enhancers and promoters bound by the hematopoietic transcription factor GATA1 (Lamonica et al., 2011; Stonestrom et al., 2015). Although BRD3 is broadly expressed, little is known about BRD3 chromatin occupancy in other tissues or its association with other tissue-specific transcription factors. |
| Function | Like BRD2 (Kanno et al., 2004) and BRD4 (Dey et al., 2003), BRD3 is associated with acetylated lysines on histones H3 and H4 (LeRoy et al., 2008). BRD3 was shown to activate transcription in vitro by promoting RNA polymerase II activity on nucleosomal templates in a manner that required the bromodomain-acetyl lysine interaction (LeRoy et al., 2008). Proteomic analysis of BET proteins indicates that BRD3 can bind to transcription elongation complexes such as PTEF-b and PAF (Dawson et al., 2011). In addition, the extraterminal (ET) domain of BRD3 can associate with the histone methyltransferase NSD3 and a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, CHD4, suggesting that BRD3 has transcriptional regulatory function in vivo as well (Rahman et al., 2011). BRD3 has also interacts with an acetylated peptide of the hematopoietic transcription factor GATA1 (Gamsjaeger et al., 2011; Lamonica et al., 2011). However, despite strong colocalization at GATA1-occupied sites genome-wide in an erythroid cell line, BRD3 depletion affected GATA1-mediated gene expression only in the setting of BRD2 loss. In addition, overexpression of BRD3 is able to partially rescue the erythroid maturation defects observed with BRD2 deficiency, suggesting that the functions of BRD2 and BRD3 are additive and at least partially redundant in erythroid cells, with BRD2 being the dominant protein (Stonestrom et al., 2015). It remains unclear how BRD2 and BRD3 can substitute for one another and whether BRD3 can functionally replace BRD2 at all genes. While knockout of BRD2 or BRD4 in mice results in early embryonic lethality (Houzelstein et al., 2002; Gyuris et al., 2009; Shang et al., 2009), a BRD3 knockout mouse has not been reported. |
| Homology | BRD3 shares functional domains with BRD2, BRD4, and BRDT. The tandem amino-terminal bromodomains, BD1 and BD2, are highly conserved between BET family members. Indeed BD1 of BRD3 is more similar to the first bromodomains of other BET proteins than it is to BD2 (Florence and Faller, 2002; Belkina and Denis, 2012). However, BET bromodomains - both BD1 and BD2 - can be selectively targeted with competitive small molecule inhibitors such as JQ1 (Filippakopoulos et al., 2010) and I-BET (Dawson et al., 2011), and thus are structurally distinct from other bromodomain-containing proteins. The carboxy-terminal extraterminal (ET) domain is about 80% conserved among BET proteins and facilitates shared protein-protein interactions with chromatin modifying proteins (Rahman et al., 2011). The remainder of the C-terminus is more divergent; however, little is understood about how this region contributes to BRD3-specific functions. BRD3, like the other BET proteins, is evolutionarily conserved in diverse species including mice and zebrafish (NCBI). In addition BET homologs exist in Drosophila as FS(1)H (Haynes et al., 1992), and in yeast, where BDF1 and BDF2 also exhibit functional redundancy (Matangkasombut and Buratowski, 2000). |
| Mutations |
| Note | Although there are 459 SNPs associated with the Brd3 mRNA transcript, only a small fraction have been validated and at present there are no clinically significant variants reported (dbSNP). Translocations involving BRD3 and Nuclear protein in testes (NUT) are found in NUT midline carcinoma (French et al., 2008), a rare squamous cell malignancy described below. |
| Implicated in |
| Note | |
| Entity | NUT midline carcinoma |
| Disease | NUT midline carcinomas (NMCs) are rare but lethal tumors consisting of undifferentiated or poorly differentiated squamous cells. Two thirds of NMCs result from a translocation of NUTM1 to the 3' end of BRD4 (t(15;19)(q14;p13) (French et al., 2003). The remaining NMCs involve a similar translocation to BRD3 (French et al., 2008) or WHSC1L1 (NSD3) (t(8;15)(p11;q14) WHSC1L1/NUTM1 )(French et al., 2014). |
| Prognosis | The first two patients in whom this translocation was described lived 148 weeks and 8 weeks post diagnosis, respectively (French et al., 2008). Median survival of all NMCs is 6.7 months (Bauer et al., 2012). |
| Cytogenetics | BRD3/NUT fusion proteins are generated from a translocation involving t(9;15)(q34;q14). NMC typically involves only a single cytogenetic abnormality, in contrast to other carcinomas (French, 2010). |
| Abnormal Protein | The predicted protein based on the mRNA analysis above is expected to contain the majority of the BRD3 protein, including the tandem bromodomains and the ET motif, attached to a version of NUT lacking the first 6 amino acids (French et al., 2008). This protein is structurally similar to that reported for BRD4-NUT (French et al., 2003). The BRD3-NUT and BRD4-NUT fusion proteins were noted to reside within the nucleus in a speckled pattern, in contrast to NUT alone, which was either cytoplasmic or nuclear. This suggests that the chromatin binding function of BRD3 and BRD4 inappropriately targets NUT to the nucleus (French et al., 2008). The reciprocal translocation product NUT-BRD3 exhibits no detectable expression (French et al., 2008). |
| Oncogenesis | The exact mechanism by which BRD3-NUT facilitates oncogenesis is not understood, but treatment of NMC cells with a BET-specific bromodomain inhibitor causes NMC cells to differentiate, suggesting that the fusion protein blocks the cells in an undifferentiated, proliferative state (Filippakopoulos et al., 2010). Deregulation of MYC expression by BRD3-NUT is one potential mechanism (Grayson et al., 2013). NUT is also known to interact with the histone acetyltransferase p300. This suggests that BRD-NUT fusion proteins can inappropriately bind p300 and redirect its activity away from its normal targets, resulting in decreased transcription of genes important for differentiation (Reynoird et al., 2010; Schwartz et al., 2011). |
| Entity | Prostate cancer |
| Disease | Depletion of BRD3 in androgen-receptor positive prostate cancer cell lines inhibited growth and invasion, suggesting that BRD3 promotes a malignant phenotype. BRD2 and BRD4 depletion had similar effects, suggesting shared functionality in this disease (Asangani et al., 2015). |
| Oncogenesis | It is not known how BRD3 promotes prostate cancer cell growth or whether this function is also important in human patients. In cell lines, BRD2, BRD3, and BRD4 can associate with the androgen receptor (AR), and global BET inhibition reduces AR chromatin binding (Asangani et al., 2015). Thus one possible mechanism is that BRD3, along with BRD2 and BRD4, may act to load or stabilize AR at its target sites. |
| Bibliography |
| Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer |
| 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 |
| Nature 2014 Jun 12;510(7504):278-82 |
| PMID 24759320 |
| Clinicopathologic features and long-term outcomes of NUT midline carcinoma |
| Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Lüer SC, Muhammed S, Evans AG, Sholl LM, Rosai J, Giraldi E, Oakley RP, Rodriguez-Galindo C, London WB, Sallan SE, Bradner JE, French CA |
| Clin Cancer Res 2012 Oct 15;18(20):5773-9 |
| PMID 22896655 |
| BET domain co-regulators in obesity, inflammation and cancer |
| Belkina AC, Denis GV |
| Nat Rev Cancer 2012 Jun 22;12(7):465-77 |
| PMID 22722403 |
| Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia |
| Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Chapman TD, Roberts EJ, Soden PE, Auger KR, Mirguet O, Doehner K, Delwel R, Burnett AK, Jeffrey P, Drewes G, Lee K, Huntly BJ, Kouzarides T |
| Nature 2011 Oct 2;478(7370):529-33 |
| PMID 21964340 |
| The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis |
| Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K |
| Proc Natl Acad Sci U S A 2003 Jul 22;100(15):8758-63 |
| PMID 12840145 |
| Selective inhibition of BET bromodomains |
| Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, Wiest O, Kung AL, Knapp S, Bradner JE |
| Nature 2010 Dec 23;468(7327):1067-73 |
| PMID 20871596 |
| You bet-cha: a novel family of transcriptional regulators |
| Florence B, Faller DV |
| Front Biosci 2001 Aug 1;6:D1008-18 |
| PMID 11487468 |
| NUT midline carcinoma |
| French CA |
| Cancer Genet Cytogenet 2010 Nov;203(1):16-20 |
| BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma |
| French CA, Miyoshi I, Kubonishi I, Grier HE, Perez-Atayde AR, Fletcher JA |
| Cancer Res 2003 Jan 15;63(2):304-7 |
| PMID 12543779 |
| NSD3-NUT fusion oncoprotein in NUT midline carcinoma: implications for a novel oncogenic mechanism |
| French CA, Rahman S, Walsh EM, Kühnle S, Grayson AR, Lemieux ME, Grunfeld N, Rubin BP, Antonescu CR, Zhang S, Venkatramani R, Dal Cin P, Howley PM |
| Cancer Discov 2014 Aug;4(8):928-41 |
| PMID 24875858 |
| Structural basis and specificity of acetylated transcription factor GATA1 recognition by BET family bromodomain protein Brd3 |
| Gamsjaeger R, Webb SR, Lamonica JM, Billin A, Blobel GA, Mackay JP |
| Mol Cell Biol 2011 Jul;31(13):2632-40 |
| PMID 21555453 |
| Association of bromodomain BET proteins with chromatin requires dimerization through the conserved motif B |
| Garcia-Gutierrez P, Mundi M, Garcia-Dominguez M |
| J Cell Sci 2012 Aug 1;125(Pt 15):3671-80 |
| PMID 22595521 |
| MYC, a downstream target of BRD-NUT, is necessary and sufficient for the blockade of differentiation in NUT midline carcinoma |
| Grayson AR, Walsh EM, Cameron MJ, Godec J, Ashworth T, Ambrose JM, Aserlind AB, Wang H, Evan GI, Kluk MJ, Bradner JE, Aster JC, French CA |
| Oncogene 2014 Mar 27;33(13):1736-42 |
| PMID 23604113 |
| The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesis |
| Gyuris A, Donovan DJ, Seymour KA, Lovasco LA, Smilowitz NR, Halperin AL, Klysik JE, Freiman RN |
| Biochim Biophys Acta 2009 May;1789(5):413-21 |
| PMID 19362612 |
| The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins |
| Haynes SR, Dollard C, Winston F, Beck S, Trowsdale J, Dawid IB |
| Nucleic Acids Res 1992 May 25;20(10):2603 |
| PMID 1350857 |
| Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4 |
| Houzelstein D, Bullock SL, Lynch DE, Grigorieva EF, Wilson VA, Beddington RS |
| Mol Cell Biol 2002 Jun;22(11):3794-802 |
| PMID 11997514 |
| Selective recognition of acetylated histones by bromodomain proteins visualized in living cells |
| Kanno T, Kanno Y, Siegel RM, Jang MK, Lenardo MJ, Ozato K |
| Mol Cell 2004 Jan 16;13(1):33-43 |
| PMID 14731392 |
| Chromosomal localization of the proteasome Z subunit gene reveals an ancient chromosomal duplication involving the major histocompatibility complex |
| Kasahara M, Hayashi M, Tanaka K, Inoko H, Sugaya K, Ikemura T, Ishibashi T |
| Proc Natl Acad Sci U S A 1996 Aug 20;93(17):9096-101 |
| PMID 8799160 |
| Bromodomain protein Brd3 associates with acetylated GATA1 to promote its chromatin occupancy at erythroid target genes |
| Lamonica JM, Deng W, Kadauke S, Campbell AE, Gamsjaeger R, Wang H, Cheng Y, Billin AN, Hardison RC, Mackay JP, Blobel GA |
| Proc Natl Acad Sci U S A 2011 May 31;108(22):E159-68 |
| PMID 21536911 |
| The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription |
| LeRoy G, Rickards B, Flint SJ |
| Mol Cell 2008 Apr 11;30(1):51-60 |
| PMID 18406326 |
| Bromodomain factor 1 corresponds to a missing piece of yeast TFIID |
| Matangkasombut O, Buratowski RM, Swilling NW, Buratowski S |
| Genes Dev 2000 Apr 15;14(8):951-62 |
| PMID 10783167 |
| Kaposi's sarcoma-associated herpesvirus LANA-1 interacts with the short variant of BRD4 and releases cells from a BRD4- and BRD2/RING3-induced G1 cell cycle arrest |
| Ottinger M, Christalla T, Nathan K, Brinkmann MM, Viejo-Borbolla A, Schulz TF |
| J Virol 2006 Nov;80(21):10772-86 |
| PMID 16928766 |
| Bromodomain testis-specific protein is expressed in mouse oocyte and evolves faster than its ubiquitously expressed paralogs BRD2, -3, and -4 |
| Paillisson A, Levasseur A, Gouret P, Callebaut I, Bontoux M, Pontarotti P, Monget P |
| Genomics 2007 Feb;89(2):215-23 |
| PMID 17049203 |
| The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3 |
| Rahman S, Sowa ME, Ottinger M, Smith JA, Shi Y, Harper JW, Howley PM |
| Mol Cell Biol 2011 Jul;31(13):2641-52 |
| PMID 21555454 |
| Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains |
| Reynoird N, Schwartz BE, Delvecchio M, Sadoul K, Meyers D, Mukherjee C, Caron C, Kimura H, Rousseaux S, Cole PA, Panne D, French CA, Khochbin S |
| EMBO J 2010 Sep 1;29(17):2943-52 |
| PMID 20676058 |
| Differentiation of NUT midline carcinoma by epigenomic reprogramming |
| Schwartz BE, Hofer MD, Lemieux ME, Bauer DE, Cameron MJ, West NH, Agoston ES, Reynoird N, Khochbin S, Ince TA, Christie A, Janeway KA, Vargas SO, Perez-Atayde AR, Aster JC, Sallan SE, Kung AL, Bradner JE, French CA |
| Cancer Res 2011 Apr 1;71(7):2686-96 |
| PMID 21447744 |
| Double bromodomain-containing gene Brd2 is essential for embryonic development in mouse |
| Shang E, Wang X, Wen D, Greenberg DA, Wolgemuth DJ |
| Dev Dyn 2009 Apr;238(4):908-17 |
| PMID 19301389 |
| Functions of BET proteins in erythroid gene expression |
| Stonestrom AJ, Hsu SC, Jahn KS, Huang P, Keller CA, Giardine BM, Kadauke S, Campbell AE, Evans P, Hardison RC, Blobel GA |
| Blood 2015 Apr 30;125(18):2825-34 |
| PMID 25696920 |
| Chromosomal localization, gene structure and transcription pattern of the ORFX gene, a homologue of the MHC-linked RING3 gene |
| Thorpe KL, Gorman P, Thomas C, Sheer D, Trowsdale J, Beck S |
| Gene 1997 Oct 24;200(1-2):177-83 |
| PMID 9373153 |
| Proteomics |
| Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Pontén F |
| Tissue-based map of the human proteome Science |
| PMID 25613900 |
| Citation |
| This paper should be referenced as such : |
| Michael T Werner, Sarah C Hsu, Gerd A Blobel |
| BRD3 (bromodomain containing 3) |
| Atlas Genet Cytogenet Oncol Haematol. 2016;20(5):238-242. |
| Free journal version : [ pdf ] [ DOI ] |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ] |
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t(9;15)(q34;q14) BRD3/NUTM1
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| External links |
| REVIEW articles | automatic search in PubMed |
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