The long-term objectives of this application are to learn more about transcriptional control in eukaryotes, using the yeasts S. cerevisiae and S. pombe as model systems. Many of the proposed studies will focus on the SAGA protein complex, initially discovered in S. cerevisiae. SAGA (Spt-Ada-Gcn5 Acetyltransferase) is a member of a class of factors, called coactivators, that play critical roles in transcriptional control. SAGA is conserved, as human SAGA-like complexes have been identified. A broad set of issues are proposed relating to transcription and to SAGA function.
Specific Aim 1 addresses the role of SAGA and other factors in oxygen-mediated transcription in S. cerevisiae. One focus is on PAU genes, expressed only anaerobically, and in a SAGA-dependent fashion. The component of SAGA required for this expression is Sgf73, the homologue of a human glutamine-expansion disease gene, ataxin-7, involved in spinocerebellar ataxia 7. Experiments will test the roles of Sgf73 in PAU induction. The other section of this aim proposes analysis of repression of ergosterol biosynthetic genes under anaerobic conditions.
Specific Aim 2 proposes experiments to study the distance constraints for activation by the SAGA-dependent activator Gal4. Experiments will study the long distance activation that can occur in particular mutants and proposes to identify additional mutants of this class.
Specific Aim 3 switches organisms, to study SAGA in the distantly related yeast, S. pombe. Genetic and biochemical approaches will be taken to elucidate the roles of SAGA in S. pombe. Other experiments will address the unexpected finding that loss of Spt3 of S. pombe causes a severe growth defect. Finally, Specific Aim 4 describes experiments to study regulation of the S. pombe inv1+ gene, highly regulated by glucose levels. Regulatory mutants will be isolated and analyzed to understand factors required for normal control of inv1+ and other glucose-repressed genes of S. pombe. These studies should reveal important aspects of transcriptional control.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular Genetics C Study Section (MGC)
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Tompkins, Laurie
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Harvard University
Schools of Medicine
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Reavey, Caitlin T; Hickman, Mark J; Dobi, Krista C et al. (2015) Analysis of Polygenic Mutants Suggests a Role for Mediator in Regulating Transcriptional Activation Distance in Saccharomyces cerevisiae. Genetics 201:599-612
Neumüller, Ralph A; Gross, Thomas; Samsonova, Anastasia A et al. (2013) Conserved regulators of nucleolar size revealed by global phenotypic analyses. Sci Signal 6:ra70
Ahn, Sejin; Spatt, Dan; Winston, Fred (2012) The Schizosaccharomyces pombe inv1(+) regulatory region is unusually large and contains redundant cis-acting elements that function in a SAGA- and Swi/Snf-dependent fashion. Eukaryot Cell 11:1067-74
Rando, Oliver J; Winston, Fred (2012) Chromatin and transcription in yeast. Genetics 190:351-87
Helmlinger, Dominique; Marguerat, Samuel; Villen, Judit et al. (2011) Tra1 has specific regulatory roles, rather than global functions, within the SAGA co-activator complex. EMBO J 30:2843-52
Hickman, Mark J; Spatt, Dan; Winston, Fred (2011) The Hog1 mitogen-activated protein kinase mediates a hypoxic response in Saccharomyces cerevisiae. Genetics 188:325-38
Winston, Fred (2009) A transcription switch toggled by noncoding RNAs. Proc Natl Acad Sci U S A 106:18049-50
Helmlinger, Dominique; Marguerat, Samuel; Villen, Judit et al. (2008) The S. pombe SAGA complex controls the switch from proliferation to sexual differentiation through the opposing roles of its subunits Gcn5 and Spt8. Genes Dev 22:3184-95
Laprade, Lisa; Rose, David; Winston, Fred (2007) Characterization of new Spt3 and TATA-binding protein mutants of Saccharomyces cerevisiae: Spt3 TBP allele-specific interactions and bypass of Spt8. Genetics 177:2007-17
Hickman, Mark J; Winston, Fred (2007) Heme levels switch the function of Hap1 of Saccharomyces cerevisiae between transcriptional activator and transcriptional repressor. Mol Cell Biol 27:7414-24

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