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

Blobel, Gerd A

Hsu, Sarah C

Werner, Michael T

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section 
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Atlas Genet Cytogenet Oncol Haematol. 2016; 20(5) 238 
Atlas of Genetics and Cytogenetics 
in Oncology and Haematology 
INIST-CNRS OPEN ACCESS JOURNAL 
BRD3 (bromodomain containing 3) 
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 
Published in Atlas Database: August 2015 
Online updated version : http://AtlasGeneticsOncology.org/Genes/BRD3ID43171ch9q34.html 
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/62771/08-2015-BRD3ID43171ch9q34.pdf  
DOI: 10.4267/2042/62771
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. 
© 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology 
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 
Other names: ORFX, RING3L 
HGNC (Hugo): BRD3 
Location: 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.   
BRD3 ((bromodomain containing 3) Werner MT, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2016; 20(5) 239 
 
 
 
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 
BRD3 ((bromodomain containing 3) Werner MT, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2016; 20(5) 240 
 
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 
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 
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 
BRD3 ((bromodomain containing 3) Werner MT, et al. 
 
 
 
 
 
Atlas Genet Cytogenet Oncol Haematol. 2016; 20(5) 241 
 
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). 
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. 
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This article should be referenced as such: 
Werner MT, Hsu SC, Blobel GA. BRD3 (bromodomain 
containing 3). Atlas Genet Cytogenet Oncol Haematol. 
2016; 20(5):238-242. 


BRD3 (bromodomain containing 3)

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BRD3 (bromodomain containing 3)

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