The long term objective of this proposal is to elucidate the function and regulation of telomerase in normal and cancer cells. Telomerase is the enzyme that replicates the DNA ends, or telomeres, of chromosomes. Normally this enzyme is repressed in most human cells, resulting in a loss of terminal DNA every cell division. This erosion of telomeres is ultimately lethal, and thus limits the lifespan of such cells. However, during the process of tumourigenesis cancer cells acquire the ability to proliferate well beyond the replicative capacity of normal cells. We and others have now shown that cancer cells appear to surmount the proliferative barrier imposed by telomere shortening through the upregulation of telomerase via the illegitimate activation of the gene hTERT, which encodes the catalytic subunit of telomerase. However, very little is know how this telomerase protein elongates telomeres, and what other proteins participate in this reaction. Additionally, mounting evidence suggests that a variety of cellular pathways may converge upon telomerase, but again how such pathways may regulate telomerase activity is uncertain. To address these issues two aims are proposed that capitalize on our previous biochemical and genetic analysis of the telomerase catalytic subunit in humans and yeast: 1. Map and characterize the functional domains of the catalytic subunit of telomerase. Identify and characterized proteins that interact with these domains. 2. Identify and characterize the human homologues of yeast proteins known to be important for telomerase function. The accomplishment of the above aims will further our understanding of how telomerase functions, of how this function is controlled and on what signals regulate this enzyme activity. Such information would be invaluable in understanding the role of telomerase in cellular immortalization which in turn could lay the foundation for the development of agents to inhibit telomerase function, which ultimately may be of therapeutic value in the treatment of human cancers.
| 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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