Telomerase is a ribonucleoprotein complex responsible for replenishing the G-rich strand of the telomere terminal repeats. It employs a small, embedded segment of a stably associated RNA component as template, and pre-existing chromosomal ends as primers to synthesize telomere tracts. Telomerase activity is specifically activated in cancer cells, and promotes neoplastic transformation by endowing cells with unlimited replicative potential. Inhibition or depletion of telomerase in tumor cells leads to telomere shortening and apoptosis, validating the potential of anti-telomerase strategies in cancer therapy. The goal of this research is to understand telomerase mechanisms and regulation using the budding yeast Saccharomyces cerevisiae as a model system. Our studies during the past funding period have yielded a wealth of information on the structure and functions of the catalytic TERT protein. In addition, they revealed (i) two telomerase-specific domains within the catalytic TERT subunit that are responsible for a unique feature of telomerase enzymology, i.e., the ability to repetitively copy a short RNA template;(ii) an alpha-helical repeat domain (named TPR) in the Est1 p subunit that possesses a novel RNA-binding activity, and (iii) regulation of telomere structure and function by an ATP-dependent chromatin remodeling complex (the INO80 complex). Based on these findings, we propose a series of biochemical, genetic and cell biological studies directed toward (1) clarifying the mechanisms and biological significance of the protein- DNA and protein-RNA interactions mediated by telomerase components, and (2) ascertaining the roles of chromatin remodeling complexes in modulating telomere structures and telomerase activity. Results from the proposed studies are expected to broaden and deepen current understandings of telomerase mechanisms and provide insights into a novel aspect of telomere regulation. Because almost all of the factors that will be examined are conserved between yeast and humans, we anticipate that many of the findings will be applicable to human telomeres and telomerase, and will facilitate the development of clinical applications based on telomere biology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062631-09
Application #
7902260
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Jones, Warren
Project Start
2001-04-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
9
Fiscal Year
2010
Total Cost
$340,956
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Yu, Eun Young; Kojic, Milorad; Holloman, William K et al. (2013) Brh2 and Rad51 promote telomere maintenance in Ustilago maydis, a new model system of DNA repair proteins at telomeres. DNA Repair (Amst) 12:472-9
Lue, Neal F; Zhou, Ruobo; Chico, Lidia et al. (2013) The telomere capping complex CST has an unusual stoichiometry, makes multipartite interaction with G-Tails, and unfolds higher-order G-tail structures. PLoS Genet 9:e1003145
Lue, Neal F; Chan, Jamie (2013) Duplication and functional specialization of the telomere-capping protein Cdc13 in Candida species. J Biol Chem 288:29115-23
Lue, Neal F; Yu, Eun Young; Lei, Ming (2013) A popular engagement at the ends. Nat Struct Mol Biol 20:10-2
Hsu, Min; Yu, Eun Young; Sprusansky, Ondrej et al. (2012) Functional analysis of the single Est1/Ebs1 homologue in Kluyveromyces lactis reveals roles in both telomere maintenance and rapamycin resistance. Eukaryot Cell 11:932-42
Sun, Jia; Yang, Yuting; Wan, Ke et al. (2011) Structural bases of dimerization of yeast telomere protein Cdc13 and its interaction with the catalytic subunit of DNA polymerase ?. Cell Res 21:258-74
Belfort, Marlene; Curcio, M Joan; Lue, Neal F (2011) Telomerase and retrotransposons: reverse transcriptases that shaped genomes. Proc Natl Acad Sci U S A 108:20304-10
Lue, Neal F; Hsu, Min (2011) A web of interactions at the ends. Mol Cell 42:269-71
Lue, Neal F (2010) Plasticity of telomere maintenance mechanisms in yeast. Trends Biochem Sci 35:8-17
Lue, Neal F; Li, Zhaohui (2007) Modeling and structure function analysis of the putative anchor site of yeast telomerase. Nucleic Acids Res 35:5213-22

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