The aim of this project is to elucidate the physical and chemical principles that underlie the function of RNA and RNA-protein machines involved in health and disease. The main subjects of study are riboswitches and ribonucleoproteins that are part of bacterial and eukaryotic messenger RNAs. Riboswitches are gene-regulatory RNAs that function by recognizing a cellular metabolite, and modulating transcription, translation, alternative splicing, or mRNA decay. They are model systems for understanding the structural basis of small molecule-RNA and RNA-RNA interactions. Of particular interest have been riboswitches that regulate synthesis of biofilms (biofilms account for a large fraction of morbidity and mortality associated with clinical procedures that employ catheters, implants, etc.), and riboswitches that sense the cell's nutritional state. The study of bacterial response to limited nutrition is important not only for future antibacterial strategies. Rather, it offers an important model system to study tissue response to physiologic insults and the growth of tumors. Many cellular RNAs function in concert with proteins, forming ribonucleoprotein complexes. We study how such complexes regulate the expression of genes ranging from telomerase (a key player in cellular senescence and immortalization) to vascular endothelial growth factor. In the past year, we have made important progress in our understanding of the mechanism of action of classes of regulatory RNAs that respond to folate starvation and to the second messenger c-di-AMP, in many bacteria including clinically important pathogens. We also have made advances in methodology for the analysis of biological RNAs.
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