Bromodomains (BRDs) are evolutionarily conserved protein–protein interaction modules. Structure-based alignments have clustered human BRDs into eight distinct families.
BRD modules share a conserved bundle of 4 α-helices (αZ, αA, αB and αC) that are linked to each other by loop segments of variable length (ZA and BC loops).
BRDs primarily recognize acetylated Lys residues on histones. Several BRDs were found to recognize acetylated non-histone proteins.
BRD-containing proteins regulate gene expression, alone or as part of larger protein complexes, through chromatin remodelling, histone modification, histone recognition and transcriptional machinery regulation.
BRD-containing proteins are frequently deregulated in cancer, and mutations in the BRDs themselves are frequently identified in a variety of cancers. BRD-containing proteins also form part of oncogenic fusion proteins that result from chromosomal rearrangements.
The development of BRD inhibitors as anticancer agents is now an intense area of research. Small-molecule inhibitors that target the bromodomain and extraterminal domain (BET) family of BRDs are now being tested in clinical trials for the treatment of various types of cancers.
Bromodomains (BRDs) are evolutionarily conserved protein–protein interaction modules that are found in a wide range of proteins with diverse catalytic and scaffolding functions and are present in most tissues. BRDs selectively recognize and bind to acetylated Lys residues — particularly in histones — and thereby have important roles in the regulation of gene expression. BRD-containing proteins are frequently dysregulated in cancer, they participate in gene fusions that generate diverse, frequently oncogenic proteins, and many cancer-causing mutations have been mapped to the BRDs themselves. Importantly, BRDs can be targeted by small-molecule inhibitors, which has stimulated many translational research projects that seek to attenuate the aberrant functions of BRD-containing proteins in disease.
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The authors apologize to all researchers whose important contributions could not be acknowledged owing to space limitations. The authors are grateful for the support for their research received from the Ludwig Institute for Cancer Research and the Structural Genomics Consortium (SGC), which is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda and the Wellcome Trust (092809/Z/10/Z). T.F. is supported by a Uehara Memorial Foundation Fellowship (201330102). P.F. is supported by a Wellcome Trust Career Development Fellowship (095751/Z/11/Z).
The authors declare no competing financial interests.
Supplementary information S1 (table)
Role(s) of BRD-containing proteins in cellular homeostasis (PDF 258 kb)
Supplementary information S2 (figure)
Structural Classification of the human BRD family. (PDF 3766 kb)
Supplementary information S3 (table)
Structures of BRD/peptide complexes (PDF 185 kb)
Supplementary information S4 (table)
Role(s) of BRD-containing proteins in cancer (mutations, expression, translocations) (PDF 307 kb)
Supplementary information S5 (table)
Mutation load of BRD modules. (PDF 2511 kb)
Supplementary information S6 (figure) (XLSX 49 kb)
Supplementary information S7 (table)
Available Chemical Tools targeting BRD modules with low nM activity (PDF 179 kb)
Supplementary information S8 (table)
Bromodomain Inhibitors in Clinical Development (data from www.clinicaltrials.gov) (PDF 162 kb)
- YEATS domains
Protein interaction domains with an immunoglobulin-like fold that can bind to acetylated and crotonylated Lys residues.
- Transcriptional co-regulators
Proteins that repress or stimulate transcription via the modulation of the activity of transcription factors through various mechanisms.
- Histone code
The epigenetic combination of histone modifications that affect transcription of genes in a hereditary fashion.
The part of a protein that can be recognized by a protein interaction domain. In the context of antibodies, it is the part of an antigen molecule to which an antibody binds.
- Epithelial–mesenchymal transition
(EMT). The process by which epithelial cells lose polarity and adhesion and acquire the invasive and migratory properties of mesenchymal cells.
Connective tissue that forms a protective layer around the heart muscle.
Portions of the chromosome that link the sister chromatids. Cohesion of the centromeres is achieved by associating with the protein cohesin, which is subsequently modified in order to keep the two sister chromatids together.
- Homeobox genes
(HOX genes). A group of related homeotic genes that control the body plan of embryos along the head–tail axis.
A short region of DNA that provides a docking site for transcriptional activators that increases the likelihood of transcription of particular genes.
- RING domain
(Really interesting new gene domain). Zinc finger domain containing a Cys3HisCys4 motif that binds two zinc ions.
- NUT midline carcinomas
Aggressive epithelial cancers that typically arise in organs in the midline of the body and result from a fusion of the NUT gene with BRD3, BRD4 or nuclear SET domain-containing gene 3 (NSD3).
Large multiprotein complex that acts as a transcriptional co-activator in eukaryotes and binds to the C-terminal domain of RNAPII, which provides a bridge between the polymerase and transcription factors.
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Fujisawa, T., Filippakopoulos, P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat Rev Mol Cell Biol 18, 246–262 (2017). https://doi.org/10.1038/nrm.2016.143
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