RNA was long thought to function solely as a genetic messenger, as a component of the ribosome, and as a carrier of amino acids. Now, largely because of research done at the University of Colorado, it is just as common to think of RNA participating actively in cellular metabolism. RNA can engage in intra-molecular catalysis, including self-splicing, and in some cases can act as an enzyme. A major goal of the work carried out by Professor Cech and his research group is to understand mechanisms of RNA catalysis at both the chemical and the biological levels. The work integrates chemistry, enzymology, molecular biology, structural biology, and genetics.

Current efforts focus on the structural biology of large catalytic RNAs, or ribozymes. Crystallographers in the Cech laboratory have grown X-ray diffraction-quality crystals of an active group I ribozyme (247 nt) and solved its structure at modest resolution (5 Ångstroms). Future work is directed toward obtaining atomic-resolution structures of active group I introns.

The structure and function of telomeres, the natural ends of linear chromosomes, provide a very different area of interest for a portion of Professor Cech's group. Major biological systems are ciliated protozoa that have an unusually large number of linear DNA molecules in their macronucleus and S. cerevisiae and S. pombe, which are amenable to genetic analysis. Members of the Cech laboratory discovered the catalytic protein subunit of telomerase and cloned and sequenced genes encoding it in Euplotes, S. pombe, human, Tetrahymena and Oxytricha. The active site protein subunits comprise a new class of reverse transcriptases, enzymes previously thought to be restricted to viruses and transposable elements. The group has also identified the Protection of Telomeres protein that caps the very ends of chromosomes in S. pombe, human, and other eukaryotes, and is investigating its sequence specificity of ssDNA binding using both biochemistry and X-ray crystallography. Long-term goals are to understand the regulation of telomerase by DNA-binding telomere proteins and to understand the nuclear localization and trafficking of telomerase.

Selected Publications

Lei, M., Podell, E. R., Baumann, P. and Cech, T. R. DNA Self-recognition in the Structure of Pot1 Bound to Telomeric Single-stranded DNA. Nature 426, 198, (2003).

Seto, A. G., Livengood, A. J., Tzfati, Y., Blackburn, E. H. and Cech, T. R. A Bulged Stem Tethers Est1p to Telomerase RNA in Budding Yeast. Genes Dev. 16, 2800-2812, (2002).

Guo, F. and Cech, T. R. Evolution of Tetrahymena Ribozyme Mutants with Increased Structural Stability. Nature Structural Biology 9, 855-961 (2002).

Baumann, P. and Cech, T. R. Pot1, the Putative Telomere End-binding Protein in Fission Yeast and Humans. Science 292, 1171-1175, (2001).

Juneau, K., Podell, E., Harrington, D. J. and Cech, T. R. RNA with Enhanced Crystallizability Identified by in vitro Evolution. Structure, 9, 221-231, (2001).