The long-term goal of this proposal is to elucidate the mechanism of telomerase-mediated telomere replication. Telomeres are DNA-protein structures essential for the stability of chromosomes. Normally, telomeric DNA is lost as human somatic cells divide, eventually leading to chromosome instability and cell death or growth arrest whereas most tumors overcome the proliferative blockade imposed by telomere shortening via the activation of the reverse transcriptase telomerase. Activation of this enzyme is critical to convert normal cells to a tumorigenic state whereas inhibition of telomerase can lead to tumor regression. Telomerase therefore plays a fundamental role in cancer, and hence it is important to understand how this enzyme is regulated. One step in regulating telomerase is the assembly of an active enzyme complex at the telomeres. Indeed, in humans, mutations to the catalytic subunit of the enzyme appear to cripple the ability of telomerase to reach telomeres, and elongate telomeric DNA. While mutants of the enzyme provide a means to identify the proteins involved in assembling an active complex at telomeres, there are also two know proteins that may play a role in telomere recruitment: hPot1, the human homolog of the telomere-binding protein Cdc13p from budding yeast, which is known to recruit telomerase to telomere via interaction with other proteins, and PinX1, a human protein that binds directly to telomerase and telomeric proteins. Capitalizing on the cloning of these two proteins and our previous work of identifying mutants of telomerase, the following three aims are proposed to dissect the regulation of telomerase in human cells:
Aim #1 : Identify proteins that interact with the domain of telomerase implicated in telomere association.
Aim #2 : Characterize the role of hPot 1 in telomere stability and replication.
Aim #3 : Characterize the role of PinX1 and its novel associated protein PXE in telomerase-mediated telomere elongation. The accomplishment of the above aims will further our comprehension of how telomerase is regulated. Such information will be invaluable in elucidating the role of telomerase in cancer, which in turn could lay the foundation for the development of agents to inhibit telomerase function, ultimately for therapeutic use cancer treatment. ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Okano, Paul
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Duke University
Schools of Medicine
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Yonekawa, Tohru; Yang, Shuqun; Counter, Christopher M (2012) PinX1 localizes to telomeres and stabilizes TRF1 at mitosis. Mol Cell Biol 32:1387-95
Stringer, Jay R; Counter, Christopher M (2012) Snm1B interacts with PSF2. PLoS One 7:e49626
Kendellen, Megan F; Barrientos, Katharine S; Counter, Christopher M (2009) POT1 association with TRF2 regulates telomere length. Mol Cell Biol 29:5611-9
Tomlinson, Rebecca L; Abreu, Eladio B; Ziegler, Tania et al. (2008) Telomerase reverse transcriptase is required for the localization of telomerase RNA to cajal bodies and telomeres in human cancer cells. Mol Biol Cell 19:3793-800
Freibaum, Brian D; Counter, Christopher M (2008) The protein hSnm1B is stabilized when bound to the telomere-binding protein TRF2. J Biol Chem 283:23671-6
Barrientos, Katharine S; Kendellen, Megan F; Freibaum, Brian D et al. (2008) Distinct functions of POT1 at telomeres. Mol Cell Biol 28:5251-64
Etheridge, Katherine T; Compton, Sarah A; Barrientos, Katharine S et al. (2008) Tethering telomeric double- and single-stranded DNA-binding proteins inhibits telomere elongation. J Biol Chem 283:6935-41
Freibaum, Brian D; Counter, Christopher M (2006) hSnm1B is a novel telomere-associated protein. J Biol Chem 281:15033-6
Poh, Melissa; Boyer, Matthew; Solan, Amy et al. (2005) Blood vessels engineered from human cells. Lancet 365:2122-4
Armbruster, Blaine N; Linardic, Corinne M; Veldman, Tim et al. (2004) Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1. Mol Cell Biol 24:3552-61

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