Structure and Function of Telomerase

Johns Hopkins University, Baltimore MD

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Telomerase is required for the maintenance of telomere length. In the absence of telomerase, telomeres shorten progressively. In primary fibroblasts telomere shortening triggers cellular senescence. This limited replicative potential may protect cells from immortalization and limit tumor growth. Telomerase is expressed at higher levels in cancer cells than somatic cells. Deletion of telomerase in mice can lead to a reduction in tumors. Telomerase is thus a prime candidate for cancer chemotherapy. Telomerase is also essential for the long-term growth of stem cells. Defects in telomerase lead to telomere shortening and stem cell failure diseases in humans. We are studying the biochemistry of telomerase and telomere processing to understand the fundamental molecular processes required for telomere length maintenance. Telomerase is a unique kind of polymerase that also contains an essential RNA component. The RNA component provides a template for the telomere repeats synthesized by telomerase. In addition, there are functional regions in the RNA that contribute to enzyme catalysis. The protein component, TElomerase Reverse Transcriptase, TERT, has a catalytic core with similarity reverse transcriptases. The domain structure and mutational analysis predict a single catalytic site for nucleotide addition. We would like to understand how the tightly bound telomerase RNA is used reiteratively as a template by copying from a single catalytic site. Further we would like to know how regions of the telomerase RNA distant from the template influence the catalytic reaction. To better understand the roles of the RNA and the protein component in elongation, we will purify the components of telomerase and study their biochemical interactions. In addition, to fully understand the regulation of telomerase elongation in vivo, we will characterize the telomere processing that creates the molecular end that is recognized by telomerase. Understanding telomerase structure, function and regulation at this molecular level will allow new approaches to both telomerase inhibition and/or telomerase activation that influence cell growth and viability. [unreadable] [unreadable] [unreadable]