Abromodomain is an approximately 110 amino acidprotein domain that recognizesacetylatedlysine residues, such as those on theN-terminal tails ofhistones. 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.[2] Their affinity is higher for regions where multiple acetylation sites exist in proximity. This recognition is often a prerequisite for protein-histone association andchromatin remodeling. The domain itself adopts anall-α protein fold, a bundle of fouralpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.[1][3]
The bromodomain was identified as a novelstructural motif by John W. Tamkun and colleagues studying theDrosophila geneBrahma/brm, and showed sequence similarity to genes involved in transcriptional activation.[4] The name "bromodomain" is derived from the relationship of this domain withBrahma and is unrelated to the chemical elementbromine.
Bromodomain-containing proteins can have a wide variety of functions, ranging from histone acetyltransferase activity and chromatin remodeling to transcriptional mediation and co-activation. Of the 43 known in 2015, 11 had two bromodomains, and one protein had 6 bromodomains.[2] Preparation, biochemical analysis, and structure determination of the bromodomain containing proteins have been described in detail.[5]
A well-known example of a bromodomain family is the BET (Bromodomain and extraterminal domain) family. Members of this family includeBRD2,BRD3,BRD4 andBRDT.[6]
However proteins such asASH1L also contain a bromodomain. Dysfunction of BRD proteins has been linked to diseases such as human squamous cell carcinoma and other forms of cancer.[7]Histone acetyltransferases, includingEP300 andPCAF, have bromodomains in addition to acetyl-transferase domains.[8][9][10]
Not considered part of the BET family (yet containing a bromodomain) areBRD7, andBRD9.
The role of bromodomains in translating a deregulated cell acetylome into disease phenotypes was recently unveiled by the development of small molecule bromodomain inhibitors. This breakthrough discovery highlighted bromodomain-containing proteins as key players in cancer biology, as well as inflammation[11] andremyelination inmultiple sclerosis.[2]
Members of the BET family have been implicated as targets in both human cancer[12][13] and multiple sclerosis.[14]BET inhibitors have shown therapeutic effects in multiple preclinical models of cancer and are currently in clinical trials in the United States.[15] Their application in multiple sclerosis is still in the preclinical stage.
Small molecule inhibitors of non-BET bromodomain proteinsBRD7 andBRD9 have also been developed.[16][17]
^Tamkun JW, Deuring R, Scott MP, Kissinger M, Pattatucci AM, Kaufman TC, Kennison JA (February 1992). "brahma: a regulator of Drosophila homeotic genes structurally related to the yeast transcriptional activator SNF2/SWI2".Cell.68 (3):561–72.doi:10.1016/0092-8674(92)90191-E.PMID1346755.S2CID27726226.
^Ren, C; Zeng, L; Zhou, MM (2016). "Preparation, Biochemical Analysis, and Structure Determination of the Bromodomain, an Acetyl-Lysine Binding Domain".Enzymes of Epigenetics, Part A. Methods in Enzymology. Vol. 573. pp. 321–43.doi:10.1016/bs.mie.2016.01.018.ISBN9780128053652.PMID27372760.
^Dhalluin, C; Carlson, J. E.; Zeng, L; He, C; Aggarwal, A. K.; Zhou, M. M.; Zhou, Ming-Ming (1999). "Structure and ligand of a histone acetyltransferase bromodomain".Nature.399 (6735):491–6.doi:10.1038/20974.PMID10365964.S2CID1210925.
^Jung, Marie; Gelato, Kathy A; Fernández-Montalván, Amaury; Siegel, Stephan; Haendler, Bernard (2015-06-16). "Targeting BET bromodomains for cancer treatment".Epigenomics.7 (3):487–501.doi:10.2217/epi.14.91.PMID26077433.
