Noncoding RNAs, such as the spliceosomal U snRNAs, transfer RNAs, ribosomal RNAs and the RNA components of signal recognition particle and telomerase, play critical roles in eukaryotic cell metabolism. Although much is known about the functions of these RNAs, little is known as to how these RNAs fold into complex structures within cells and how cells handle misfolded and defective RNAs. Our long term objective is to understand the cellular requirements for productive RNA folding and to uncover the mechanisms by which cells detect and degrade defective RNAs. Our specific strategy is to focus on proteins that interact with nascent RNAs, using genetics and biochemistry in the yeast Saccharomyces cerevisiae. Our previous work revealed that a conserved protein, the La protein, protects nascent noncoding RNAs from nucleases, assists pre-tRNA folding and interfaces with a surveillance pathway for defective RNAs. We also described a complex of Sm-like proteins that functions in the biogenesis or function of a subset of nucleolar RNAs. Our goal now is to dissect the molecular mechanisms by which La and other proteins assist noncoding RNA biogenesis and quality control.
Our first aim i s to use biochemistry, genetics and structural biology to determine how La stabilizes correctly folded RNAs.
Our second aim i s to elucidate the role of La in noncoding RNA surveillance.
Our third aim i s to characterize several mutations that increase the abundance of unstable noncoding RNAs. Cloning of the mutant genes and characterization of their products should reveal new players in noncoding RNA quality control.
Our fourth aim i s to purify the Sm-like protein complex and determine its role in the yeast nucleolus. As much of gene expression is mediated through noncoding RNAs, an understanding of RNA biogenesis and quality control should be of broad importance for uncovering mechanisms by which cells escape normal growth controls and for designing new therapeutics. Lay summary: Although noncoding RNAs are critical for cell function, little is known as to how these RNAs are made and how cells detect and remove RNAs that contain errors. By understanding these processes, it may be possible to design treatments for diseases caused by noncoding RNAs that do not function properly.
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