| The reversible acetylation of histones plays a critical role in the transcriptional regulation in eukaryotic cells, and there is mounting evidence that acetylation of non-histone substrates is important for other cellular processes. Two families of deacetylase enzymes have been identified: the histone deacetylases, or HDACs, and the Sir-2 like family of NAD-dependent deacetylases, or sirtuins. Herein is described the cloning and preliminary characterization of the three founding members (HDAC4, 5, and 6) of a distinct class of HDAC proteins. The ability of all previously described HDACs to repress transcription is regulated by targeting them to specific promoters or chromosomal domains via interactions with DNA-binding proteins. An additional regulatory mechanism was characterized for two of these newly identified HDACs, in which they are inactivated by phosphorylation-dependent sequestration. Finally, the first synthetic small molecule inhibitor of the sirtuin family of deacetylases was identified from a screen of 1600 unbiased compounds. This small molecule should provide a useful tool for the elucidation of sirtuin function in a wide variety of organisms. |
