BRD9

Last updated March 12, 2019

Bromodomain-containing protein 9 is a protein that in humans is encoded by the BRD9 gene. ^[1]

Protein biological molecule consisting of chains of amino acid residues

Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific three-dimensional structure that determines its activity.

In biology, a gene is a sequence of nucleotides in DNA or RNA that codes for a molecule that has a function. During gene expression, the DNA is first copied into RNA. The RNA can be directly functional or be the intermediate template for a protein that performs a function. The transmission of genes to an organism's offspring is the basis of the inheritance of phenotypic trait. These genes make up different DNA sequences called genotypes. Genotypes along with environmental and developmental factors determine what the phenotypes will be. Most biological traits are under the influence of polygenes as well as gene–environment interactions. Some genetic traits are instantly visible, such as eye color or number of limbs, and some are not, such as blood type, risk for specific diseases, or the thousands of basic biochemical processes that constitute life.

Structure and interaction

BRD9 contains a bromodomain. It is closely related to BRD7. BRD9 is present in some SWI/SNF ATPase remodeling complexes.^[2]

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.

Bromodomain-containing protein 7 is a protein that in humans is encoded by the BRD7 gene.

In molecular biology, SWI/SNF, is a nucleosome remodeling complex found in eukaryotes. In simpler terms, it is a group of proteins that associate to remodel the way DNA is packaged. It is composed of several proteins – products of the SWI and SNF genes as well as other polypeptides. It possesses a DNA-stimulated ATPase activity and can destabilise histone-DNA interactions in reconstituted nucleosomes in an ATP-dependent manner, though the exact nature of this structural change is unknown.

Role in cancer

The BRD9 gene is frequently present in variable copy number in lung cancer.^[3]

Small molecule inhibition

Small molecules capable of binding to the bromodomain of BRD9 have been developed.^[4]^[5]^[6]

Related Research Articles

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

Transcription activator BRG1 also known as ATP-dependent chromatin remodeler SMARCA4 is a protein that in humans is encoded by the SMARCA4 gene.

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 is a protein that in humans is encoded by the SMARCB1 gene.

Probable global transcription activator SNF2L2 is a protein that in humans is encoded by the SMARCA2 gene.

AT-rich interactive domain-containing protein 1A is a protein that in humans is encoded by the ARID1A gene.

SWI/SNF complex subunit SMARCC1 is a protein that in humans is encoded by the SMARCC1 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

SWI/SNF complex subunit SMARCC2 is a protein that in humans is encoded by the SMARCC2 gene.

AT-rich interactive domain-containing protein 1B is a protein that in humans is encoded by the ARID1B gene. ARID1B is a component of the human SWI/SNF chromatin remodeling complex.

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 is a protein that in humans is encoded by the SMARCD1 gene.

Bromodomain-containing protein 4 is a protein that in humans is encoded by the BRD4 gene.

Protein polybromo-1 (PB1) also known as BRG1-associated factor 180 (BAF180) is a protein that in humans is encoded by the PBRM1 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 localizes to 9q34, a region which contains several major histocompatibility complex (MHC) genes.

Bromodomain testis-specific protein is a protein that in humans is encoded by the BRDT gene. It is a member of the Bromodomain and Extra-terminal motif (BET) protein family.

JQ1 is a thienotriazolodiazepine and a potent inhibitor of the BET family of bromodomain proteins which include BRD2, BRD3, BRD4, and the testis-specific protein BRDT in mammals. BET inhibitors structurally similar to JQ1 are being tested in clinical trials for a variety of cancers including NUT midline carcinoma. It was developed by the James Bradner laboratory at Brigham and Women's Hospital and named after chemist Jun Qi. The chemical structure was inspired by patent of similar BET inhibitors by Mitsubishi Tanabe Pharma [WO/2009/084693]. Structurally it is related to benzodiazepines. While widely used in laboratory applications, JQ1 is not itself being used in human clinical trials because it has a short half life.

RVX 208 is an orally available small molecule created by Resverlogix Corp. that is being evaluated in clinical trials for the treatment of atherosclerosis and associated cardiovascular disease (CVD). In two phase II clinical trials in patients with established CVD, apabetalone increased HDL-cholesterol (HDL-c) and apolipoprotein A-I (ApoA-I) levels, as well as decreased the incidence of major adverse cardiac events (MACE). Reduction of MACE was more profound in patients with diabetes mellitus. In a short term study in prediabetics, favorable changes in glucose metabolism were observed in patients receiving apabetalone. An international, multicenter phase III trial, “Effect of RVX000222 on Time to Major Adverse Cardiovascular Events in High-Risk Type 2 Diabetes Mellitus Subjects with Coronary Artery Disease” (BETonMACE) commenced in October 2015. The trial is designed to determine whether apabetalone in combination with statins can decrease cardiac events compared to treatment with statins alone.

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

References

↑ "Entrez Gene: Bromodomain containing 9".
↑ Kadoch, C; Hargreaves, D. C.; Hodges, C; Elias, L; Ho, L; Ranish, J; Crabtree, G. R. (2013). "Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy". Nature Genetics. 45 (6): 592–601. doi:10.1038/ng.2628. PMC 3667980  . PMID 23644491.
↑ Kang, J. U.; Koo, S. H.; Kwon, K. C.; Park, J. W.; Kim, J. M. (2008). "Gain at chromosomal region 5p15.33, containing TERT, is the most frequent genetic event in early stages of non-small cell lung cancer". Cancer Genetics and Cytogenetics. 182 (1): 1–11. doi:10.1016/j.cancergencyto.2007.12.004. PMID 18328944.
↑ Fedorov, O; Lingard, H; Wells, C; Monteiro, O. P.; Picaud, S; Keates, T; Yapp, C; Philpott, M; Martin, S. J.; Felletar, I; Marsden, B. D.; Filippakopoulos, P; Müller, S; Knapp, S; Brennan, P. E. (2014). "1,2,4triazolo4,3-aphthalazines: Inhibitors of diverse bromodomains". Journal of Medicinal Chemistry. 57 (2): 462–76. doi:10.1021/jm401568s. PMC 3906316  . PMID 24313754.
↑ Clark, P. G.; Vieira, L. C.; Tallant, C; Fedorov, O; Singleton, D. C.; Rogers, C. M.; Monteiro, O. P.; Bennett, J. M.; Baronio, R; Müller, S; Daniels, D. L.; Méndez, J; Knapp, S; Brennan, P. E.; Dixon, D. J. (2015). "LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor". Angewandte Chemie International Edition. 54: 6217–6221. doi:10.1002/anie.201501394. PMC 4449114  . PMID 25864491.
↑ Theodoulou, N. H.; Bamborough, P; Bannister, A. J.; Becher, I; Bit, R. A.; Che, K. H.; Chung, C. W.; Dittmann, A; Drewes, G; Drewry, D. H.; Gordon, L; Grandi, P; Leveridge, M; Lindon, M; Michon, A. M.; Molnar, J; Robson, S. C.; Tomkinson, N. C.; Kouzarides, T; Prinjha, R. K.; Humphreys, P. G. (2015). "The Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition". Journal of Medicinal Chemistry: 150430080108003. doi:10.1021/acs.jmedchem.5b00256. PMID 25856009.

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[entrez-1] "Entrez Gene: Bromodomain containing 9".

[2] Kadoch, C; Hargreaves, D. C.; Hodges, C; Elias, L; Ho, L; Ranish, J; Crabtree, G. R. (2013). "Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy". Nature Genetics. 45 (6): 592–601. doi:10.1038/ng.2628. PMC 3667980  . PMID 23644491.

[3] Kang, J. U.; Koo, S. H.; Kwon, K. C.; Park, J. W.; Kim, J. M. (2008). "Gain at chromosomal region 5p15.33, containing TERT, is the most frequent genetic event in early stages of non-small cell lung cancer". Cancer Genetics and Cytogenetics. 182 (1): 1–11. doi:10.1016/j.cancergencyto.2007.12.004. PMID 18328944.

[4] Fedorov, O; Lingard, H; Wells, C; Monteiro, O. P.; Picaud, S; Keates, T; Yapp, C; Philpott, M; Martin, S. J.; Felletar, I; Marsden, B. D.; Filippakopoulos, P; Müller, S; Knapp, S; Brennan, P. E. (2014). "1,2,4triazolo4,3-aphthalazines: Inhibitors of diverse bromodomains". Journal of Medicinal Chemistry. 57 (2): 462–76. doi:10.1021/jm401568s. PMC 3906316  . PMID 24313754.

[5] Clark, P. G.; Vieira, L. C.; Tallant, C; Fedorov, O; Singleton, D. C.; Rogers, C. M.; Monteiro, O. P.; Bennett, J. M.; Baronio, R; Müller, S; Daniels, D. L.; Méndez, J; Knapp, S; Brennan, P. E.; Dixon, D. J. (2015). "LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor". Angewandte Chemie International Edition. 54: 6217–6221. doi:10.1002/anie.201501394. PMC 4449114  . PMID 25864491.

[6] Theodoulou, N. H.; Bamborough, P; Bannister, A. J.; Becher, I; Bit, R. A.; Che, K. H.; Chung, C. W.; Dittmann, A; Drewes, G; Drewry, D. H.; Gordon, L; Grandi, P; Leveridge, M; Lindon, M; Michon, A. M.; Molnar, J; Robson, S. C.; Tomkinson, N. C.; Kouzarides, T; Prinjha, R. K.; Humphreys, P. G. (2015). "The Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition". Journal of Medicinal Chemistry: 150430080108003. doi:10.1021/acs.jmedchem.5b00256. PMID 25856009.