Bromodomain and extra-terminal domain protein (BET protein family; refers collectively to four main proteins: BRD2, BRD3, BRD4, and BRDT) (BET protein (BET))

The BET protein family comprises four conserved nuclear proteins in mammals: BRD2, BRD3, BRD4, and BRDT. They feature two N-terminal bromodomains (BD1 and BD2), which recognize and bind acetylated lysine residues on histones and other proteins, and a C-terminal extra-terminal (ET) domain involved in recruiting regulatory cofactors[1][3][4]. BET proteins function as "epigenetic readers" that interpret acetylation marks to regulate gene transcription, chromatin remodeling, RNA processing, and DNA repair[1][3][9][6]. They participate as central scaffolds for assembling transcriptional machinery (including RNA polymerase II) at active gene promoters and enhancers, and coordinate global gene expression in a context-dependent manner[3][4][10]. BET proteins have distinct as well as overlapping roles in physiology: BRD2, BRD3, and BRD4 are widely expressed, while BRDT is restricted to testis[1][3]. Inhibitors targeting BET bromodomains are under active investigation for cancer, inflammation, cardiovascular, and neurodegenerative disorders, with multiple small molecules, such as JQ1 and OTX-015, in clinical and preclinical studies[5][7][8]. Safety profiles remain a consideration, as on-target adverse effects and resistance have emerged as major clinical challenges[5].

Other names

Bromodomain and extra-terminal motif proteinBET proteinBRD2BRD3BRD4BRDT

Competitive inhibition of bromodomains (prevents BET proteins from binding acetylated histone lysines) Disruption of recruitment of transcriptional machinery at gene promoters/enhancers Inhibition of transcription elongation Modulation of super-enhancer activity