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 Life expectancy in industrialized countries has nearly doubled during the 20 th century. Longer life expectancy leads to the increased risk of exposure to age-related disorders, including neurodegeneration and cancer, and the associated healthcare related costs. Molecular mechanisms mediating the cellular changes that occur during ageing, and age-related diseases include oxidative stress, DNA damage, genomic instability, telomere reduction, and cell death.
One requirement for cell proliferation and survival is telomere integrity; unstable telomeres lead to chromosome degradation, end-to-end chromosome fusions, and the activation of DNA damage checkpoints. Telomere integrity is maintained by (i) telomeric proteins which mediate the formation of a protective cap structure, and (ii) primarily the enzyme telomerase, or a recombination pathway termed alternative lengthening of telomeres (ALT). Human telomerase is composed of a catalytic subunit (hTERT) and an RNA component (hTR) that provides the template for the synthesis of repeated G-rich d(TTAGGG)n telomere sequences. Telomere integrity can be jeopardized by extensive telomere shortening in the absence of a telomere maintenance mechanism, or by alteration of the protective cap. Dysfunctional telomeres may contribute to the development of aging phenotypes, such as vascular disease, poor wound healing, and immunosenescence. In the genetic syndrome dyskeratosis congenita, caused by defects in the telomerase complex, telomere shortening is accelerated, and patients have premature onset of several age-related disorders and early death. Furthermore, ectopic expression of hTERT in telomerase-negative primary cells constitutively expressing hTR induces telomerase activity, lengthens telomeres and extends cellular life span, but does not induce changes associated with malignant transformation. Concomitant alteration of key cellular proteins (p53, pRb, H-Ras) can convert primary cells into tumorigenic cells, indicating that telomerase activation and telomere maintenance are critical steps for immortalization and tumorigenesis. Notably, telomerase is expressed in 85% of human cancers. Understanding the regulation of cell survival and tumorigenesis by telomere maintenance and telomerase will lead to the identification of targets with potential therapeutic applications to prevent age- or disease-related cell death, and for inducing cancer cell death.
The long-term objective of my research is the development of (i) anti-cancer therapies that target telomerase or telomere integrity, and (ii) efficacious treatments of age or disease-related cell death. Our short-term objectives are to: 1) Characterize the mechanisms that regulate telomerase, telomere length and cell survival, including associated proteins, enzyme processivity, and alternative splicing of the TERT telomerase component; 2) evaluate the principles of anti-cancer strategies that target telomerase or telomere integrity, by validating novel ligands which stabilize G-quadruplex structures at telomeres, and through studies to understand the regulation of telomere maintenance by recombination in telomerase-negative cancer cells and in telomerase-positive cancer cells in which telomere function is targeted.
SOME RECENT PUBLICATIONS:
Fakhoury, J., Marie-Egyptienne, D.T., Londoño-Vallejo J.A. and Autexier, C. 2010. Telomeric function of mammalian telomerases at short telomeres. J. Cell Science. 123, 1693-704.
Marie-Egyptienne, D.T., Brault, M.E., Nimmo, G.A.M., Londoño-Vallejo J.A.and Autexier, C. 2009. Growth defects in mouse cells expressing mutant-template mouse telomerase RNA. Cancer Lett. 275, 266-276. MEDLINE link to this publication
Kieltyka, R., Englebienne, P., Fakhoury, J., Autexier, C., Moitessier, N., and Sleiman, H. 2008. A platinum supramolecular square as an effective G-Quadruplex binder and telomerase inhibitor. J. Am. Chem. Soc. 130, 10040-10041. MEDLINE link to this publication
Marie-Egyptienne, D.T., Brault, M.E., Zhu, S. and Autexier, C. 2008. Telomerase inhibition in a mouse cell line with long telomeres leads to rapid telomerase reactivation. Exp. Cell Res. 314, 668-675. MEDLINE link to this publication
Autexier, C. 2008. POT of gold: modeling dyskeratosis congenita in the mouse. Genes & Development, 22, 1731-1736. MEDLINE link to this publication
Shawi, M. and Autexier, C. 2008. Telomerase, senescence and aging. Mechanisms of Ageing and Development, 129, 3-10. MEDLINE link to this publication
Fakhoury, J., Nimmo, G.A.M. and Autexier, C. 2007. Harnessing telomerase in cancer therapeutics. Anti-Cancer Agents in Medicinal Chemistry 7, 475-483. MEDLINE link to this publication
Brault, M.E., D’Souza, Y. and Autexier, C. 2007. Telomerase structure, function and evolution. In: Origin and Evolution of Telomeres. Lubo Tomaska and Jozef Nosek, eds. Eureka.com and Kluwer Academic/Plenum Publishers, New York, NY.
Jain, P., Cerone, M.A, LeBlanc, A.C. and Autexier, C. 2007. Telomerase and neuronal marker status of differentiated NT2 and SK-N-SH human neuronal cells and primary human neurons. Journal of Neuroscience Research, 85, 83-89. MEDLINE link to this publication
Marie-Egyptienne, D.T. and Autexier, C. 2006. Anomalies du complexe de la télomérase en pathologie hématologique. Hématologie, 12, 267-273.
Autexier, C. and Lue, N.F. 2006. The structure and function of Telomerase Reverse Transcriptase (TERT). Annual Review of Biochemistry, 75, 493-517. MEDLINE link to this publication
Cerone M.A., Londono-Vallejo J.A. and Autexier C. 2006. Mutated telomeres sensitize tumor cells to anti-cancer drugs independently of telomere shortening and mechanisms of telomere maintenance. Oncogene 25, 7411-7420. MEDLINE link to this publication
Cerone M.A., Londono-Vallejo J.A. and Autexier C. 2006. Telomerase inhibition enhances the response to anti-cancer drug treatment in human breast cancer cells. Molecular Cancer Therapeutics, Mol. Cancer Ther. 5,1669-1675. MEDLINE link to this publication
Marie-Egyptienne, D.T., Cerone, M.A. and Autexier, C. 2005. A human-Tetrahymena pseudoknot chimeric telomerase RNA reconstitutes a nonprocessive enzyme in vitro that is defective in telomere elongation. Nucl. Acids Res., 33, 5446-5457. MEDLINE link to this publication
Moriarty, T.J. Marie-Egyptienne, D.T. and Autexier, C. 2005. Regulation of the 5' template usage and incorporation of non-cognate nucleotides by human telomerase. RNA, 11, 1448-1460. MEDLINE link to this publication
Cerone M.A., Autexier, C. Londono-Vallejo J.-A. and Bacchetti, S. 2005. A human cell line that maintains telomeres in the absence of telomerase and of key markers of ALT. Oncogene. 24, 7893-7901. MEDLINE link to this publication
Lue N.F., Bosoy D., Moriarty T.J., Autexier C., Altman B., Leng S. 2005. Telomerase can act as a template- and RNA-independent terminal transferase. Proc Natl Acad Sci USA. 102, 9778-9783. MEDLINE link to this publication
Ward, R.J. and Autexier, C. 2005. Pharmacological Telomerase Inhibition can Sensitize Drug-Resistant and Drug-Sensitive Cells to Chemotherapeutic Treatment. Mol. Pharmacol. 68, 779-786
Moriarty, T.J., Ward, R.J. Taboski, M.A.S. Autexier, C. 2005. An Anchor Site-type Defect in Human Telomerase that Disrupts Telomere Length Maintenance and Cellular Immortalization. Mol Biol Cell. 16, 3152-3161. MEDLINE link to this publication
Cerone M.A., Ward R.J., Londono-Vallejo J.A., Autexier C. 2005. Telomerase RNA Mutated in Autosomal Dyskeratosis Congenita Reconstitutes a Weakly Active Telomerase Enzyme Defective in Telomere Elongation. Cell Cycle. 4, 585-589. MEDLINE link to this publication
Cerone, M.A., Ward, R.J. and Autexier, C. 2005. Telomere and Telomerase-based Therapies. In: Aging Interventions and Therapies. Suresh I.S. Rattan, ed. World Scientific Publishers, Singapore.
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