Human telomerase, the ribonucleoprotein enzyme that maintains telomeres at chromosome termini, is absent in most normal somatic cells and is present in nearly all cancer cells. Activation of telomerase induces cellular immortalization and is critical for the development and progression of tumors. Thus, inhibition of telomerase activity offers a promising approach for treating nearly all cancers. A better understanding of telomerase is needed to allow rational design of effective inhibitors. In humans, telomerase includes two subunits essential for function: an RNA subunit (human telomerase RNA) and a protein subunit (human telomerase reverse transcriptase). The location and mechanism of assembly of the enzyme complex in cancer cells (which may indicate where and how to target telomerase) is not known. Furthermore, identification of additional essential components of telomerase would provide additional potential targets for inhibition. The major objectives of this proposal are to obtain a detailed understanding of the trafficking and assembly of telomerase in cells, and to develop a class of RNA-based telomerase inhibitors effective at limiting or preventing the growth of cancer cells. In vivo analysis will be performed both in Xenopus oocytes (due to the many technical advantages of the system) and cultured human cells (including primary and cancer cell lines). To address our objectives we have defined the following three specific aims:
Aim 1 : To investigate the pathway of biogenesis of functional telomerase in vivo Aim 2: To examine the localization and trafficking of key human telomerase components in normal and cancer cells Aim 3: To develop efficacious anti-telomerase ribozymes capable of preventing growth of cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104676-04
Application #
7237884
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Pelroy, Richard
Project Start
2004-08-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2007
Total Cost
$228,899
Indirect Cost
Name
University of Georgia
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Abreu, Eladio; Terns, Rebecca M; Terns, Michael P (2011) Visualization of human telomerase localization by fluorescence microscopy techniques. Methods Mol Biol 735:125-37
Zhao, Yong; Abreu, Eladio; Kim, Jinyong et al. (2011) Processive and distributive extension of human telomeres by telomerase under homeostatic and nonequilibrium conditions. Mol Cell 42:297-307
Abreu, Eladio; Aritonovska, Elena; Reichenbach, Patrick et al. (2010) TIN2-tethered TPP1 recruits human telomerase to telomeres in vivo. Mol Cell Biol 30:2971-82
Li, Zhu-Hong; Tomlinson, Rebecca L; Terns, Rebecca M et al. (2010) Telomerase trafficking and assembly in Xenopus oocytes. J Cell Sci 123:2464-72
Tomlinson, Rebecca L; Li, Jian; Culp, Bradley R et al. (2010) A Cajal body-independent pathway for telomerase trafficking in mice. Exp Cell Res 316:2797-809
Venteicher, Andrew S; Abreu, Eladio B; Meng, Zhaojing et al. (2009) A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 323:644-8
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
Cristofari, Gael; Adolf, Emem; Reichenbach, Patrick et al. (2007) Human telomerase RNA accumulation in Cajal bodies facilitates telomerase recruitment to telomeres and telomere elongation. Mol Cell 27:882-9
Terns, M; Terns, R (2006) Noncoding RNAs of the H/ACA family. Cold Spring Harb Symp Quant Biol 71:395-405