Bromodomain-containing protein 4 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''BRD4''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes

BRD2 Bromodomain-containing protein 2 is a protein that in humans is encoded by the ''BRD2'' gene. BRD2 is part of the Bromodomain and Extra-Terminal motif (BET) protein family that also contains BRD3, BRD4, and BRDT in mammals Early descriptions dem ...

, BRD3, and BRDT. BRD4, similar to other BET family members, contains two bromodomains that recognize

acetylated : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposit ...

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

residues. BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members.

Structure

The two bromodomains in BRD4, termed BD1 and BD2, consist of 4

alpha-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

linked by 2 loops. The ET domain structure is made up of 3 alpha-helices and a loop. The C-terminal domain of BRD4 has been implicated in promoting

gene transcription Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...

through interaction with the transcription elongation factor

P-TEFb The positive transcription elongation factor, P-TEFb, is a multiprotein complex that plays an essential role in the regulation of transcription by RNA polymerase II (Pol II) in eukaryotes. Immediately following initiation Pol II becomes trapped in ...

and

RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryo ...

Function

The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human

(RING3) protein, a

serine/threonine kinase A serine/threonine protein kinase () is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human prote ...

. Each of these proteins contains two bromodomains, a conserved

sequence motif In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an ''N''-glycosylation site motif can be defined as ''As ...

which may be involved in

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

targeting. This gene has been implicated as the chromosome 19 target of translocation t(15;19)(q13;p13.1), which defines the

NUT midline carcinoma NUT carcinoma (NC; formerly NUT midline carcinoma (NMC)) is a rare genetically defined, very aggressive squamous cell epithelial cancer that usually arises in the midline of the body and is characterized by a chromosomal rearrangement in the nucle ...

. Two alternatively spliced transcript variants have been described.

Role in cancer

Most cases of

involve translocation of the ''BRD4'' gene with ''NUT'' genes. BRD4 is often required for expression of ''

Myc ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' (MYC), ''l-myc'' ( MYCL), and ''n-myc'' (MYCN). ''c-myc'' (also sometimes refe ...

'' and other "tumor driving" oncogenes in hematologic cancers including

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...

acute myelogenous leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may includ ...

and acute lymphoblastic leukaemia. BRD4 is a major target of

BET inhibitors BET inhibitors are a class of drugs that reversibly bind the bromodomains of BET protein, Bromodomain and Extra-Terminal motif (BET) proteins BRD2, BRD3, BRD4, and BRDT, and prevent protein-protein interaction between BET proteins and acetylated hi ...

, a class of pharmaceutical drugs currently being evaluated in clinical trials.

Interactions

Notably, BRD4 interacts with

via its P-TEFb interaction domain (PID), thereby stimulating its kinase activity and stimulating its phosphorylation of the carboxy-terminal domain (CTD) of

. Recent review. BRD4 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with

GATA1 GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by ...

JMJD6 Bifunctional arginine demethylase and lysyl-hydroxylase JMJD6 is an enzyme that in humans is encoded by the ''JMJD6'' gene. Function This gene encodes a nuclear protein with a JmjC domain. JmjC domain-containing proteins belong to the alpha-ke ...

RFC2 Replication factor C subunit 2 is a protein that in humans is encoded by the ''RFC2'' gene. Function The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins, proliferating cell ...

RFC3 Replication factor C subunit 3 is a protein that in humans is encoded by the ''RFC3'' gene. Function The elongation of primed DNA templates by DNA polymerase delta and DNA polymerase epsilon requires the accessory proteins proliferating cell ...

RFC1 Replication factor C subunit 1 is a protein that in humans is encoded by the ''RFC1'' gene. Function The protein encoded by this gene is the large subunit of replication factor C, which is a five subunit DNA polymerase accessory protein. Replic ...

RFC4 Replication factor C subunit 4 is a protein that in humans is encoded by the ''RFC4'' gene. Function The elongation of primed DNA templates by DNA polymerase delta and DNA polymerase epsilon requires the accessory proteins proliferating cell ...

and

RFC5 Replication factor C subunit 5 is a protein that in humans is encoded by the ''RFC5'' gene. Function The elongation of primed DNA templates by DNA polymerase delta and DNA polymerase epsilon requires the accessory proteins proliferating cell ...

. BRD4 has also been implicated in binding with the diacetylated

Twist Twist may refer to: In arts and entertainment Film, television, and stage * ''Twist'' (2003 film), a 2003 independent film loosely based on Charles Dickens's novel ''Oliver Twist'' * ''Twist'' (2021 film), a 2021 modern rendition of ''Olive ...

protein, and the disruption of this interaction has been shown to suppress tumorigenesis in basal-like breast cancer. BRD4 has also been shown to interact with a variety of inhibitors, such as MS417; inhibition of BRD4 with MS417 has been shown to down-regulate

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...

activity seen in HIV-associated kidney disease. BRD4 also interacts with apabetalone (RVX-208), which is being evaluated for treatment of

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...

and

cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...

Structure

Function

Role in cancer

Interactions

References

External links

Further reading