Molecular dissection of eukaryotic transcription termination mechanisms

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A great challenge for a eukaryotic cell is to produce the appropriate amount of each protein and to quickly adjust that production as the cell's environment changes. To meet this challenge, cells must orchestrate many discrete steps, but the details of this integration are not well understood. This research will use baker's yeast as a model to explore the molecular interactions cells use to mount an integrated response to environmental stress. Because all organisms must cope with stresses of various types, the results should be applicable to other systems and may aid in developing strategies for engineering stress tolerance. In addition to advancing scientific knowledge, this project will provide opportunities for training undergraduates, post-baccalaureate trainees, and graduate students from diverse backgrounds. It will improve STEM education by providing research opportunities for junior faculty from primarily undergraduate institutions at critical points in their careers. The project will also provide training in computational science as a quantitative and predictive tool for biological studies, and develop a publicly available web interface for researchers to explore aspects of gene regulation using whole genome datasets. Proper responses to cellular stress require coordination among a number of gene expression steps. These include different phases of mRNA synthesis--initiation, elongation and termination--as well as multiple steps in processing, such as capping, splicing, polyadenylation, all culminating with export of the mRNA from the nucleus. Each part of this "coordination network" constitutes a step at which the amount and type of mRNA from a particular gene can be regulated. The goal of this project is to use the yeast Saccharomyces cerevisiae as a model organism to identify critical molecular interactions that coordinate transcription and mRNA 3' end processing. In particular, the project will use complementary approaches of molecular biology, biochemistry, genetics, and bioinformatics to determine how core polyadenylation factors contribute to the activation and repression of genes in response to stress. The results should provide new insights into the mechanisms cells use to rapidly fine-tune their responses to changing environmental conditions.