Histone Acetyltransferases Discovery and Biomedical Perspectives

Inhibitors of Histone Acetyltransferases Discovery and Biomedical Perspectives 

In 1963 J.H. Rubinstein and H. Taybi reported a rare human disease that induced mental retardation, an increased risk of neoplasia and physical abnormalities, including broad thumbs, big and broad toes, short stature and craniofacial anomalies. The molecular basis of the Rubinstein-Taybi syndrome (RTS) was later discovered to be a disruption of one copy of the human CREB binding protein (CBP or CREB-BP) gene that encodes the histone acetyltransferase CBP [3]. In addition to CBP, all mammals have a closely related acetyltransferase, p300. Retrospectively, RTS was the first disease found to be due to a defective acetylation process [1-3]. 

HATs catalyze the post-translational acetylation of amino-terminal lysine tails of core histones, which results in disruption of the repressive chromatin folding and an increased DNA accessibility to regulatory proteins. The level of histone acetylation is highly controlled and balanced by the activity of histone deacetylases (HDACs), the opponents of HATs. Generally, acetylation is correlated with activation and deacetylation with repression of gene expression. Therefore, the dynamic equilibrium of these proteins represents a key mechanism of gene regulation. 

It should be noted that HATs and HDACs are not only limited to histones, but rather various nonhistone proteins can be acetylated/deacetylated as well [2, 4]. Many regulators of DNA repair, recombination and replication, viral proteins, classic metabolic enzymes (e.g. bacterial and mammalian acetyl-CoA synthases) and 

GNAT Gcn5 Yeast, human H2B, H4, cMYC Coactivator 

---