Control of Histone Function in Yeast

University Of California Los Angeles, Los Angeles CA

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Abstract

The histone H3 and H4 termini help regulate cell cycle progression, gene[unreadable] activity and nucleosome assembly. These functions are likely to be[unreadable] mediated by acetylation and deacetylation of these N terminal tails which[unreadable] may not only affect their interactions with underlying DNA but with other[unreadable] proteins. We have recently discovered the family of five histone[unreadable] deacetylases in yeast which have different and overlapping roles in H3 and[unreadable] H4 acetylation, cell cycle progression and gene activity. Our goal now is[unreadable] to define these roles at a molecular level. We proposed to identify[unreadable] catalytic and regulatory non-catalytic subunits of each of these complexes[unreadable] since these factors may determine deacetylase specificity to different[unreadable] sites in histones, different genes and different stages of the cell cycle.[unreadable] We wish to know the extent to which deacetylase regulates un-induced and[unreadable] induced gene activity and whether this occurs through effects on[unreadable] nucleosome positioning, DNA topology or chromosomal condensation. Since[unreadable] nucleosome structure is disrupted at promoters by activators even before[unreadable] transcription and since histone acetylation provides a logical mechanism[unreadable] for nucleosome disruption, we propose to determine whether a known[unreadable] acetyltransferase (TAF130), that is part of the transcription machinery,[unreadable] disrupts nucleosome at promoters. Finally, we will determine which sites[unreadable] of acetylation in H3 and H4 are important for nucleosome assembly.[unreadable] Understanding gene activity and the cell cycle is central to our knowledge[unreadable] of human disease processes. Chromatin modifications affect both. Moreover,[unreadable] disruption of a histone deacetylase by a drug has been identified as a[unreadable] means of selectively inactivating parasites involved in diseases such as[unreadable] malaria and toxoplasmosis. The molecular characterization of the multiple[unreadable] histone deacetylases in yeast will allow the design of rational approaches[unreadable] to combat these disease states.[unreadable]