The snoRNAs (small nucleolar RNAs) comprise a large family of trans-acting RNAs that guide the modification (and in some cases cleavage) of ribosomal RNAs, small nuclear RNAs, and perhaps messenger RNAs. As such, the snoRNAs are essential for the production of spliceosomes and ribosomes - the mRNA splicing and protein translation machinery of the cell. A deficiency in the expression of some snoRNAs has been linked with the neurogenetic disease Prader-Willi Syndrome, and deletion of other snoRNAs is lethal. The goal of this project is to determine how the snoRNAs assemble with proteins into functional complexes (snoRNPs) and are transported within the cell. We will employ a combination of biochemical, cytological, and genetic approaches and will exploit two systems (Xenopus laevis oocytes and Saccharomyces cerevisiae) for in vivo studies. We will investigate the organization of core snoRNP proteins on each of two functional classes of snoRNPs in vivo, establishing a necessary framework for understanding the assembly and function of snoRNPs. In addition, we will investigate the roles of accessory proteins in the assembly and transport of snoRNPs. One protein that we will focus on, SMN, is linked to spinal muscular atrophy, a fatal recessive genetic disease with an incidence of approximately 1 in 10,000 human births. Our work will investigate the normal cellular functions of SMN and other proteins. Finally, we will characterize gene products identified in directed genetic screens in order to understand their roles in snoRNP biogenesis and intracellular trafficking. The insight that we gain into the mechanisms by which RNAs are transported will provide a foundation for understanding the trafficking of all RNAs that pass through the nucleus and for rational targeting of RNA-based therapeutic agents being developed to treat a wide range of human infections and diseases. ? ?
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