Methylarginine Dynamics in Cellular Processes

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Organisms depend on nutrients to grow and proliferate, but the availability of such resources can be limiting at times. This situation represents a stress on a cellular level. The response to this type of stress is studied in the unicellular organism Saccharomyces cerevisiae, commonly referred to as baker's yeast. Research has emerged that cells experiencing nutrient deprivation undergo significant changes to ensure their long-term survival through the winter of their discontent. Under these conditions, cells break down and recycle their components within a vacuole compartment in a process called autophagy, which is necessary for extending the lifespan of the organism. The amino acid arginine is stored in the vacuole and used as one of many protein building blocks. My laboratory studies a methyltransferase enzyme family that attaches small carbon units to the ends of arginine within proteins. This simple modification exerts profound cellular effects by altering molecular interactions. The long-term objective of my program of research is to determine how methyltransferase activity affects a broad set of cellular processes, and specifically for this NSERC proposal in the short-term, how the methylated arginine metabolites from autophagy affect cell survival and lifespan. In our investigation into the yeast response to nutrient deprivation, we found significant changes on methylated arginine outside of cells that was dependent on which gene was deleted. We plan to show that this amino acid efflux is a product of autophagy, and that preventing methylated arginine efflux from yeast under stress compromises important processes required for long-term survival. We will search for and characterize new arginine methyltransferases in yeast whose gene deletions impact the efflux of specific methylarginine species. The broad range of state-of-the-art, cell-based, and biochemical methods required to achieve the goals of the research program will provide analytical, communication, and time management skills for HQP that will make them competitive within Canada's natural sciences community and productive in its knowledge-driven economy. I intend on training a diverse group of three qualified HQP recruited with an awareness around equity and inclusiveness with this NSERC award. Together, our findings will have a profound effect on our understanding of how methylarginine metabolism affects cell survival in yeast for a global network of researchers studying arginine methyltransferases, autophagy, and aging.