Elucidating the molecular and cellular functions of polyamines

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PROJECT SUMMARY Polyamines are small organic compounds with two or more amine groups. These evolutionarily ancient metabolites are essential for a variety of cellular processes, including cell growth and survival, and are present at milli-molar concentrations in mammalian cells. Cellular polyamine concentrations are tightly regulated, and changes in polyamine levels disrupt numerous cellular processes, including DNA compaction, transcription, translation, autophagy, and stress response. Disruption of polyamine metabolism is also observed in several diseases. Genetic mutations in polyamine metabolic pathways are linked with learning disability in Snyder- Robinson syndrome and are a known risk factor for Parkinson's disease. Polyamine levels are elevated in many cancers, and there is enormous interest in using this pathway as a chemotherapeutic target. Mechanistically, how disruption of polyamine metabolism affects cell function and produces disease is not known. The precise biochemical functions of polyamines in the cell remain mysterious. This gap in our knowledge stems from intrinsic technological difficulties in probing polyamines. This project will deliver new methods and conceptual frameworks to elucidate the molecular functions of polyamines. One, we will develop new quantitative assays to measure polyamine concentrations in living cells. Two, we will investigate how mammalian cells maintain polyamine homeostasis and identify the proteins involved in their uptake. Third, we will examine how changes in cellular polyamine levels affect RNA localization, structure, and translation. By delivering new technologies and functional frameworks, this work will advance our understanding of the roles of polyamines in the cell, and may help unlock the pharmacological potential of these metabolites in health and curing disease.