ABSTRACT
Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as "readers" of histone lysine acetylation, a component of the proposed "histone code". Bromodomain-containing proteins are often found as components of larger protein complexes with roles in fundamental cellular process including transcription. The publication of two potent ligands for the BET bromodomains in 2010 demonstrated that small molecules can inhibit the bromodomain-acetyl-lysine protein-protein interaction. These molecules display strong phenotypic effects in a number of cell lines and affect a range of cancers in vivo. This work stimulated intense interest in developing further ligands for the BET bromodomains and the design of ligands for non-BET bromodomains. Here we review the recent progress in the field with particular attention paid to ligand design, the assays employed in early ligand discovery, and the use of computational approaches to inform ligand design.
Subject(s)
Histones/metabolism , Lysine/metabolism , Nuclear Proteins/antagonists & inhibitors , Protein Processing, Post-Translational/drug effects , Small Molecule Libraries/pharmacology , Acetylation , Animals , Humans , Ligands , Models, Molecular , Nuclear Proteins/genetics , Protein Binding , Protein Structure, Tertiary , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
Telomeres protect the eukaryotic chromosome ends from degradation and fusion. They are maintained by the ribonucleoprotein telomerase, the core of which is composed of a reverse transcriptase (TERT) and a RNA subunit. In the yeast Saccharomyces cerevisiae, a third critical telomerase subunit, the Ever Shorter Telomeres 1 (EST1) gene product, recruits or activates telomerase at the 3' end of telomeres. Est1p has so far only been known in budding yeast, and mechanisms that mediate telomerase access and activation in other eukaryotes have remained elusive. Here, we use iterative profile searches to identify homologs of yeast Est1p in a large variety of eukaryotes, including human. One of three human homologs, designated human EST1A (hEST1A), is shown to be associated with most or all active telomerase in HeLa cell extracts. Overexpression of hEST1A induces anaphase bridges due to chromosome-end fusions, and telomeric DNA persists at the fusion points. Thus, overexpression of hEST1A affects telomere capping. The identification of EST1 homologs in a large variety of eukaryotes may indicate that the mechanisms of telomere extension are more conserved than anticipated previously.
