HDACs deacetylate histones

HDACs are often part of multi-protein transcriptional complexes that are recruited to gene promoters, regulating transcription without direct DNA binding. With the exception of HDAC8, all class I members can be catalytic subunits of multiprotein complexes. HDAC1 and HDAC2 interact to form the catalytic core of several multisubunit complexes including Sin3, nucleosome remodeling deacetylase (NuRD) and corepressor of REST (CoREST) complexes. HDAC3 is part of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complex or the homologous nuclear receptor corepressor (NCoR) which are involved in a wide range of processes including metabolism, inflammation, and circadian rhythms.

Class IIa HDACs (HDAC4, -5, -7, and -9) shuttle between the nucleus and cytoplasm. The nuclear export of class IIa HDACs requires phosphorylation stimulated by calcium or other stimuli. They appear to have been evolutionarily inactivated as enzymes, having acquired a histidine substitution of the tyrosine residue in the active site of the mammalian deacetylase domain (H976 in humans). Instead they function as transcriptional corepressors for the MEF2 family of transcription factors.

Histones are the primary substrate for most HDACs except HDAC6 which is predominantly cytoplasmic and acts on alpha-tublin. HDACs also deacetylate proteins such as p53, E2F1, RelA, YY1, TFIIE, BCL6 and TFIIF.

Histone deacetylases are targeted by structurally diverse compounds known as HDAC inhibitors (HDIs). These can induce cytodifferentiation, cell cycle arrest and apoptosis of transformed cells. Some HDIs have significant antitumor activity and at least two are approved anti-cancer drugs.

The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.