Impact of chemical modification of non-coding RNAs on gene expression in S. pombe

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Cells have evolved a number of diverse mechanisms by which they ensure the stable expression of genes that are critical to life, as well as complex schemes by which they can vary such processes in order to adapt to environmental conditions and stresses. Many of these mechanisms and processes are highly conserved throughout evolution. It is often then much simpler and more straight-forward to study these critical processes using single-celled eukaryotes from which we can then extrapolate insights into how related processes are controlled in higher eukaryotes, like humans. In our proposed work, we plan to use the simple yeast Schizosaccharomyces pombe to investigate how specific chemical reactions contribute to the stable maintenance of components of the intracellular machinery that are used to control gene expression. More specifically, we propose to study a number of conserved but poorly characterized enzymes that are responsible for the chemical modification of RNA molecules that comprise critical components of the gene expression infrastructure.  One class of enzymes we will study is responsible for the chemical modification of transfer RNAs (tRNAs), which are molecules that play critical roles in the synthesis of proteins in all life forms examined. These enzymes are hypothesized to promote tRNA stability and play a role in tRNA quality control, and so our proposed work will lead to new insights into how cells ensure that the machinery used to synthesize proteins is correctly generated.  We also plan to investigate another class of methyltransferases that modify other types of non-coding RNAs but whose precise function and importance are not well understood.  The evolutionary conservation of these enzymes is unusual: they are present in some organisms but not others, even though the known targets of the enzyme are universal and critically important to cellular growth.   By studying the evolutionary conservation of these RNA modification enzymes and their targets in Schizosaccharomyces pombe, we will arrive at a better understanding of how life has evolved to promote robust synthesis of the machinery used to express genes as well as the quality control mechanisms in place to ensure this is done correctly. The elucidation of these mechanisms in yeast will be useful in extrapolating related pathways in higher organisms, and may assist in the generation of new tools for genetic engineering, as well in the design of new anti-microbials.