Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene. [3] [4]
BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes BRD2, BRD3, and BRDT. [5] BRD4, similar to other BET family members, contains two bromodomains that recognize acetylated lysine residues. [6] BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members. [5]
The two bromodomains in BRD4, termed BD1 and BD2, consist of 4 alpha-helices linked by 2 loops. [7] The ET domain structure is made up of 3 alpha-helices and a loop. [8] The C-terminal domain of BRD4 has been implicated in promoting gene transcription through interaction with the transcription elongation factor P-TEFb and RNA polymerase II. [9] [10] [11]
The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human BRD2 (RING3) protein, a serine/threonine kinase. Each of these proteins contains two bromodomains, a conserved sequence motif which may be involved in chromatin 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. Two alternatively spliced transcript variants have been described. [4]
Most cases of NUT midline carcinoma involve translocation of the BRD4 gene with NUT genes. [12] BRD4 is often required for expression of Myc and other "tumor driving" oncogenes in hematologic cancers including multiple myeloma, acute myelogenous leukemia and acute lymphoblastic leukaemia. [13]
BRD4 is a major target of BET inhibitors, [13] [14] a class of pharmaceutical drugs currently being evaluated in clinical trials.
Notably, BRD4 interacts with P-TEFb via its P-TEFb interaction domain (PID), thereby stimulating its kinase activity and stimulating its phosphorylation of the carboxy-terminal domain (CTD) of RNA polymerase II. [15] Recent review. [16]
BRD4 has been shown to interact with GATA1, [17] JMJD6, [18] RFC2, [19] RFC3, [19] RFC1, [19] RFC4 [19] and RFC5. [19]
BRD4 has also been implicated in binding with the diacetylated Twist protein, and the disruption of this interaction has been shown to suppress tumorigenesis in basal-like breast cancer. [20]
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 activity seen in HIV-associated kidney disease. [21] BRD4 also interacts with apabetalone (RVX-208), [22] which is being evaluated for treatment of atherosclerosis and cardiovascular disease.
Papillomaviridae is a family of non-enveloped DNA viruses whose members are known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected mammals, but also other vertebrates such as birds, snakes, turtles and fish. Infection by most papillomavirus types, depending on the type, is either asymptomatic or causes small benign tumors, known as papillomas or warts. Papillomas caused by some types, however, such as human papillomaviruses 16 and 18, carry a risk of becoming cancerous.
Bookmarking refers to a potential mechanism of transmission of gene expression programs through cell division.
A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the N-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. Their affinity is higher for regions where multiple acetylation sites exist in proximity. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.
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 in eukaryotes. Immediately following initiation Pol II becomes trapped in promoter proximal paused positions on the majority of human genes. P-TEFb is a cyclin dependent kinase that can phosphorylate the DRB sensitivity inducing factor (DSIF) and negative elongation factor (NELF), as well as the carboxyl terminal domain of the large subunit of Pol II and this causes the transition into productive elongation leading to the synthesis of mRNAs. P-TEFb is regulated in part by a reversible association with the 7SK snRNP. Treatment of cells with the P-TEFb inhibitors DRB or flavopidirol leads to loss of mRNA production and ultimately cell death.
In molecular biology 7SK is an abundant small nuclear RNA found in metazoans. It plays a role in regulating transcription by controlling the positive transcription elongation factor P-TEFb. 7SK is found in a small nuclear ribonucleoprotein complex (snRNP) with a number of other proteins that regulate the stability and function of the complex.
Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb.
Cyclin-T1 is a protein that in humans is encoded by the CCNT1 gene.
Transcription elongation factor SPT5 is a protein that in humans is encoded by the SUPT5H gene.
Interferon regulatory factor 2 is a protein that in humans is encoded by the IRF2 gene.
Replication factor C subunit 1 is a protein that in humans is encoded by the RFC1 gene.
Replication factor C subunit 4 is a protein that in humans is encoded by the RFC4 gene.
Replication factor C subunit 2 is a protein that in humans is encoded by the RFC2 gene.
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
Replication factor C subunit 3 is a protein that in humans is encoded by the RFC3 gene.
Replication factor C subunit 5 is a protein that in humans is encoded by the RFC5 gene.
Cyclin-T2 is a protein that in humans is encoded by the CCNT2 gene.
Bromodomain-containing protein 3 (BRD3) also known as RING3-like protein (RING3L) is a protein that in humans is encoded by the BRD3 gene. 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.
In molecular biology, the NELF is a four-subunit protein complex that negatively impacts transcription by RNA polymerase II by pausing about 20-60 nucleotides downstream from the transcription start site (TSS).
Epigenetics of human development is the study of how epigenetics effects human development.
In genetics, transcriptional amplification is the process in which the total amount of messenger RNA (mRNA) molecules from expressed genes is increased during disease, development, or in response to stimuli.
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