application) Gene expression in eukaryotes is often under the control of multiple nuclear proteins that work in combination to regulate transcription. The combined interactions between proteins often create a new form of regulatory activity that is distinct from either protein alone. The interactions between these proteins dictate which DNA target sites are bound and therefore which sets of genes are regulated. In some cases, thes protein interactions also influence whether a regulatory protein functions as transcriptional activator or repressor. Understanding the mechanism of how these proteins interact in different combinations, and how these interactions determine the activity and specificity of the complex, will provide insight into the regulation of many developmental and cellular processes. In this project three simple regulatory systems in the yeast Saccharomyces cerevisiae will be investigated for their mechanisms of combinatorial control (1) The alpha2 repressor, a homeodomain protein, interacts with the Mcml and a proteins to turn off two different sets of cell type specific-genes in yeast. The Pi will investigate how alpha2 recognizes the DNA on its own, and how the interactions with Mcml and al influence the target specificity of the complex (Specific aim 1). (2) Mcml, a MADS-box protein, interacts with at least five different co-factor to regulate different sets of genes that are required for cellular processes ranging from cell mating type and arginine metabolism to cell-cycle control. The PI will investigate how Mcml binds DNA on its own (Specific aim 2) and interacts with these co-factors to regulate these diverse sets of genes (Specific aim 3). (3) Pho2, a homeodomain protein, interacts with the Pho4, Bas 1 and Swi5 proteins to regulate genes required for phosphate metabolism, amino acid biosynthesis and cell type switching, respectively. The investigator proposes to investigate how Pho2 binds DNA on its own and interacts with these differen co-factors (Specific aim 4). The proteins in these simple regulatory systems are similar in structure and function to proteins found in mammals and plants. The information learned abou the interactions between these different classes of proteins is expected to be relevant to more complex systems in higher eukaryotes and to provide insight into how these proteins function.
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