Telomeres protect linear eukaryotic chromosomes from terminal degradation or fusion and can regulate gene expression and possibly cellular senescence. The telomeric DNA simple sequence repeats required for these functions are maintained in a dynamic balance between loss of terminal repeats with genome replication and their addition de novo. The enzyme telomerase, a reverse transcriptase, extends chromosome termini by addition of one strand of simple sequence repeat DNA. The sequence specificity of repeat addition is provided by a template sequence within the integral RNA component of the enzyme. While the template RNA has been identified and isolated from a number of species including ciliates, yeasts, and mammals, none of the protein components of telomerase have been identified from any organism, until now. The investigator has recently shown that telomerase from the ciliated protozoan Tetrahymena is composed of two protein subunits (p80 and p95) in addition to the 159-nt template RNA. In addition, she has cloned the genes for these two novel proteins. Dr. Collins proposes studies to examine the structure and function of Tetrahymena telomerase in vitro. She plans to determine RNA and protein sequences required for the novel polymerase properties of this enzyme and for RNA- and DNA-protein interactions. Telomerase enzyme mutant in specific properties will then be expressed in Tetrahymena, to test the significance of the affected properties in vivo. It has been suggested that normal human somatic tissues do not express telomerase activity and that this loss of activity may explain why these cells have only a finite proliferative lifespan. In contrast, malignant cancer cells do express telomerase activity and perhaps due to this can avoid proliferative senescence. Thus while understanding the mechanism of DNA synthesis by this novel ribonucleoprotein polymerase is an important investigation in its own right, these experiments also have direct implications for the improvement of human health.
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