The long-term goals of this project are to contribute to the understanding of (1) how structured RNA molecules can catalyze biochemical reactions in the absence of proteins, and (2) how RNA participates in catalysis in concert with proteins. In the first broad area, the crystal structure of a domain of the Tetrahymena group I ribozyme will be used to design and interpret biochemical studies of RNA tertiary structure formation. The structural basis of a conformational change involved in switching from step 1 to step 2 of RNA self-splicing will be investigated. Finally, the structure and mechanism of a peptidyl transferase ribozyme will be analyzed. Structure-function relationships in ribozymes are related to health because RNA viruses, retroviruses, and cellular mRNAs involved in disease require specific RNA structures. The second broad area concerns telomerase, the RNA-protein (RNP) enzyme required for chromosome end replication in diverse eukaryotes. Studies of telomerase structure and assembly in Saccharomyces cerevisiae and Schizosaccharomyces pombe will integrate genetic and biochemical approaches. A major focus is the Telomerase Reverse Transcriptase (TRT) subunit (known in S. cerevisiae as Ever Shorter Telomeres 2), implicated as the catalytic subunit of telomerase in many organisms including humans. Reconstitution of active telomerase RNP from purified recombinant components and understanding interactions of telomerase with its telomeric substrate present as a DNA-protein complex are major goals. Because telomerase is inactive in most human somatic cells but reactivated in most tumors, analysis of this enzyme may contribute to development of anti-telomerase chemotherapeutics.
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