La function and the unfolded protein response

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The capacity to adapt to environmental stresses is critical for the viability of all life forms. The molecular players and pathways by which microbes respond to stress are often evolutionarily conserved in higher organisms. A major goal of my research program is to identify the mechanisms underlying the activation and regulation of an evolutionarily conserved stress adaptation known as the unfolded protein response (UPR) in the genetically and biochemically tractable model organism, Schizosaccharomyces pombe (fission yeast). The UPR is found in all higher organisms and is used to overcome a number of environmental challenges. Furthermore, the ability activate an effective UPR has been implicated in disease states. For several metabolic processes, fission yeast has been characterized as the most representative microbe in terms of evolutionary conservation with higher organisms, but its UPR remains to be described. One direction of my research program is to address this knowledge gap and provide significant insight into the regulation of the UPR in S. pombe and the nature of its evolutionary conservation and divergence. A separate but related element of my research program involves the La protein. This conserved cellular factor is critical to the normal maturation of various nucleic acid species (tRNAs) in the cell and also controls the expression of certain gene products at the RNA level. Importantly, it is thought to regulate the UPR through as yet unknown mechanisms. As my previous work has shown extensive conservation of La function between fission yeast and higher organisms, including humans, my research program will focus on delineating the function of this protein in the UPR of S. pombe and in the regulation of other RNAs more generally. The results of the proposed work will be used to develop comprehensive models for genetic regulation in stress responses. The elucidation of mechanisms of stress adaptation in S. pombe will be useful in extrapolating related pathways in higher organisms, and may provide insight into the characterization of microbial growth conditions and the design of new anti-microbials.