The overall objective of the proposed research program is to contribute to our understanding of how eukaryotic mRNA molecules move from the nucleus to the cytoplasm. The presence of methylated arginine residues in heterogeneous nuclear ribonucleoproteins (hnRNPs), which have been implicated in RNA export, suggests that the activities of these proteins may be modulated by methylation. In spite of the identification of arginine methyltransferases in eukaryotes from yeast to mammals, the importance of arginine dimethylation in hnRNP-dependent processes remains unknown and is a central focus of this research proposal. Biochemical, cell biological and genetic approaches in the yeast Saccharomyces cerevisiae will be used to test whether arginine methylation affects: 1) protein-RNA interactions, 2) protein-protein interactions, and 3) shuttling of methylated RNA-binding proteins between the nucleus and the cytoplasm. In addition, other genes involved in arginine methylation will be identified. By understanding the regulation of nucleocytoplasmic transport, one may identify new targets for anti-viral and anti-cancer therapies. While HIV and other viruses exploit the endogenous nuclear import and export machinery during their replicative cycles, this machinery is also required for cells to respond to signals for proliferation. Cancer results from cellular proliferation becoming independent of environmental signals. Thus if protein methylation is found to help regulate nucleocytoplasmic transport, methods to alter the activity of methyltransferases could prove useful in treating cancer and/or viral infection.
