The numerous small RNAs in eukaryotic cells include the spliceosomal U snRNAs, the RNA component of the signal recognition particle, the telomerase RNA, transfer RNAs and 5S ribosomal RNA. Although much is known about the functions of many of these RNAs, far less is known about how these RNAs are processed from larger precursors, folded arid assembled into functional RNA-protein complexes. The focus of the work proposed here are several proteins that play critical roles in the biogenesis of small RNAs. One protein under study, the La autoantigen, is the first protein that associates with many small RNAs immediately after their synthesis. Experiments in the yeast Saccharomyces cerevisiae have suggested the yeast La protein Lhplp functions as a molecular chaperone to facilitate the correct fate of newly transcribed small RNAs in vivo. Other proteins under study are members of the Sm and Sm-like families of proteins, which are required for the stable accumulation of the spliceosomal U small nuclear RNAs. Our research addresses three broad questions. First, what are the mechanisms by which binding by Lhplp to nascent RNAs facilitates small RNA processing, folding and RNP assembly? Second, how do Sm-like proteins contribute to the biogenesis and function of their associated RNAs? Third, how do Sm proteins bind their substrate RNAs, and what other proteins function in the snRNP assembly process? The proposed studies should expand our knowledge of RNA biogenesis by providing much needed insights into the processes of RNA folding and RNP assembly. Furthermore, since both the La and the Sm proteins are major autoantigens in patients with systemic lupus erythematosus, our work may provide clues as to why proteins that function in the earliest steps of small RNA biogenesis are targets of the autoimmune response.
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