The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men

Abstract

In the past decade, protein Lys acetylation has emerged as a major post-translational modification that occurs even in bacteria. This modification not only regulates chromatin-templated nuclear processes, but also controls classical metabolism, cytoskeleton dynamics, apoptosis, protein folding and cellular signalling in the cytoplasm. Lys deacetylases, the enzymes that are responsible for reversing this modification, are divided into the Rpd3/Hda1 (or classical) and sirtuin families, with the classical family having 11 members in mammals. These members are referred to as histone deacetylases (HDAC) 1–11. HDAC1, HDAC2 and HDAC3 are deacetylase subunits of multiprotein complexes that are crucial for chromatin modification and epigenetic landscaping. These complexes comprise subunits that are required for interplay with other chromatin modifications such as DNA and histone methylation, as well as with ATP-dependent chromatin remodelling. HDAC4, HDAC5, HDAC7 and HDAC9 are novel signal transducers that are tightly regulated by phosphorylation-dependent nucleocytoplasmic trafficking. Conceptually, they are similar to the cytokine-stimulated STAT and TGFβ-regulated SMAD signal-responsive transcription factors. By binding to ubiquitin and deacetylating α-tubulin, cortactin and HSP90, HDAC6 regulates various cytoplasmic processes including cytoskeleton dynamics, ciliogenesis, aggresome formation, autophagy, nuclear receptor maturation and, possibly, endocytosis of Tyr kinase receptors. HDAC inhibitors are promising therapeutic agents for cancer and other major diseases, as evidenced by the recent approval of one such inhibitor for the treatment of cutaneous T-cell lymphoma.