Abstract
The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code. BET proteins play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes. On the other hand, BET proteins have been reported to mediate latent viral infection in host cells and be involved in oncogenesis. Human BRD4 is involved in multiple processes of the DNA virus life cycle, including viral replication, genome maintenance, and gene transcription through interaction with viral proteins. Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes. BET bromodomain blockade using small-molecule inhibitors gives rise to selective repression of the transcriptional network driven by c-MYC These inhibitors are expected to be potential therapeutic drugs for a wide range of cancers. This review presents an overview of the basic roles of BET proteins and highlights the pathological functions of BET and the recent developments in cancer therapy targeting BET proteins in animal models.
Highlights
In Drosophila, the maternal effects gene, fsh, plays critical roles in establishing segments and specifying their identities during embryonic development [1]
This review focuses on the basic functions of the four paralogous Bromodomain and Extra-Terminal Domain (BET) proteins, which are summarized in Table 1 together with the pathological functions of the proteins
These proteins have a common feature of epigenetic transcriptional regulators that recognize acetylated lysines in histones through their bromodomains and control the movement of RNA Pol II on chromatin
Summary
In Drosophila, the maternal effects gene, fsh, plays critical roles in establishing segments and specifying their identities during embryonic development [1]. BRD4 plays crucial roles in controlling cell growth by regulating the expression of transcription factors [8] This regulation requires recognition of the histone acetylation code by the Brd bromodomains [19]. Brd functions on distal enhancers as well as on gene bodies by interacting with the acetylated histones through bromodomains [24,25]. A genome wide approach for the characterization of nucleosomes decoded by the double bromodomain BET factors shows that direct binding of BRD4 to acetylated nucleosomes associated with transcribed genes is required for their proper expression [26]. Phylogenetic analysis of genes in these MHC paralogous regions shows that several rounds of genome-wide duplications occurred after the divergence of cephalochordates and vertebrates but before the jawed vertebrate (Gnathostomata) radiation [11]
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