Biogenesis, Function and Turnover of Noncoding RNAs

Division Of Basic Sciences - Nci

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Abstract

The long-term goals of our laboratory are to understand how noncoding RNAs fold into complex structures and function within cells, how cells recognize and degrade misfolded and otherwise defective noncoding RNAs, and how failure to degrade defective RNAs affects cell function and contributes to disease. A major focus are two RNA chaperones, the La and Ro60 proteins, that were first discovered because they are clinically important targets of autoantibodies in patients with two systemic rheumatic diseases, systemic lupus erythematosus and Sjögren's syndrome. La binds some newly made noncoding RNAs and assists their folding and ribonucleoprotein assembly. While there is good evidence that La can assist RNA folding, the mechanisms by which La executes this function have been unknown. Ro60 is a ring-shaped protein that is found complexed with some misfolded RNAs in animal cell nuclei. Although structural studies revealed that the ends of misfolded RNAs insert thought its central cavity, how Ro60 binding affects the structures and fates of misfolded RNAs has been unknown. This year we collaborated with Susan Lea's laboratory to obtain cryo-EM structures of Ro60 and La bound to misfolded RNA. The structures, together with additional biochemical experiments, reveal that Ro60 and La function synergistically to unfold non-native structural elements. In addition to its role in recognizing misfolded RNAs, Ro60 binds noncoding RNAs called Y RNAs. Our studies of Ro60/Y RNA complexes in bacteria and mammalian cells have revealed that one role of Y RNAs it to tether Ro60 to effector proteins, such as nucleases, helicases, and RNA chaperone proteins. We continue to identify additional functions for Ro60 and Y RNAs in mammalian cells. As part of this effort, we have identified RNA and protein partners of individual Ro60/Y RNA complexes in mouse and human cells.