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 We study two essential biological "nanomachines", RNA polymerase II (Pol II) and the spliceosome, using yeast as a model system. Our work on Pol II focuses on transcription termination as a strategy for gene regulation. We discovered a pathway that uses the helicase Sen1 and a collection of RNA-binding proteins to terminate Pol II transcrition close to the promoter. This pathway produces functional non-coding RNAs and regulates mRNA synthesis by attenuation. We use genetics, genomics, cell biology and biochemistry to define the mechanism and targets of the Sen1-dependent termination pathway. Mutations in the human Sen1 homolog cause motor neuron degeneration.

We use yeast as a surrogate to study the effects of these mutations. Our studies on the spliceosome focua on U6 RNA and the dyamic RNA-RNA and RNA-protein interactions required for its assembly into the archive site. Using genetic suppression analysis and in vitro biochemistry, we have defined a complex network of interactions that involves 3 RNAs (U2, U4, and U6), two helicases (Prp28 and Brr2), an RNA-binding progein (Prp24), and the largest and most conserved spliceosomal protein (Prp8). In collaboration with the Butcher and Phillips labs, we are determining the NMR and crystal structures of these slicing factors and their complexes, starting with U6 and Prp24.

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