Bromodomain-containing protein 2, 3, and 4 (BET family) (BRD2/3/4)

Bromodomain-containing protein 2 (BRD2), BRD3, and BRD4 are members of the Bromodomain and Extra-Terminal (BET) family of epigenetic readers. These proteins possess two highly conserved N-terminal bromodomains (BD1 and BD2) that specifically recognize and bind to acetylated lysine residues on histone tails and transcription factors (UniProt P25440, Q15059, O60885). By acting as scaffolds, they recruit transcriptional machinery, including the Positive Transcription Elongation Factor b (P-TEFb) and the Mediator complex, to promote the expression of genes involved in cell growth and survival (Filippakopoulos et al., Nature 2010). In many cancers, BET proteins are dysregulated or involved in chromosomal translocations, leading to the constitutive activation of oncogenes such as MYC and BCL2 (Shi & Vakoc, Mol Cell 2014). Small-molecule inhibitors targeting these bromodomains have shown significant therapeutic potential by inducing growth arrest and apoptosis in various hematologic and solid tumors. Beyond oncology, BET proteins play critical roles in modulating inflammatory responses and are being investigated for roles in cardiovascular and metabolic diseases (Cochran et al., MedChemComm 2019).

Other names

Bromodomain and extra-terminal domain proteinsBET proteinsRING3ORFXMCAPHUNK1

Competitive inhibition of the bromodomains (BD1 and BD2) prevents the binding of BET proteins to acetylated lysine residues on histone tails, which disrupts the recruitment of transcriptional regulatory complexes such as P-TEFb and Mediator to chromatin, ultimately suppressing the expression of downstream target genes like MYC.