EXCEED THE SPACE PROVIDED. A universal challenge faced by all livingorganisms is to identify and then attept to counteract the deleterious effects of environmental stresses. Whether multicellular or unicellular, all organisms ranging from bacteria to mammals, have evolved mechanisms to deal with such molecular insults. Indeed the fundamental mechanisms for responding to such agents as ionizing radiation, oxidative stress, mutagenic and toxic small molecules, nutrient deprivation and temperature extremes (heat shock) have been highly evolutionarily conserved at the molecularlevel. A cardinal feature of all of these molecular-cellularprotectivemechanisms is that transcriptionof certain cellulargenes encoding proteinsthat conferstress-protective properties is induced. Concomitantly,transcriptionof genes encoding proteins (and RNAs) that lack protective cellular/moleculareffects is repressed. These criticaltranscriptionalresponsesare all mediated throughthe actions of a handfulof distincttranscriptionalactivator and repressor proteins. In this studywe propose to use state of the art multidimensionaltandem mass spectrometry methods to identify and molecularly characterize the protein-proteinregulatory networksconnectingthe environmentwith key conserved transcriptionfactors knownto drive the gene-level protectivechanges in cellular RNA synthesis. Our studies will initiallyfocus uponthe geneticallytractable and simple eukaryote Baker'syeast (Saccharomyces cerevisiae). However, inthe latter phase of this project we will apply the knowledgegained in the unicellular yeast model system to human cells. PERFORMANCE SITE ========================================Section End===========================================
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