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 Telomeres,
the ends of chromosomes, serve as protective caps that prevent
chromosomes from fusing together and causing DNA rearrangements
that can lead to karyotypic changes and genomic instability. Conventional
semi-conservative DNA replication does not allow for the completion
of chromosome ends, so telomere length is predicted to decrease
with successive rounds of cell division and replication. In ciliates,
mammals, vertebrates and yeast, telomere synthesis and replication
are generally catalyzed by telomerase, a specialized reverse transcriptase
that maintains telomere length by balancing telomere shortening
with telomere elongation. Telomerase is a ribonucleoprotein (RNP)
in which part of the RNA component provides the template for the
synthesis of telomeric sequences. In Tetrahymena and yeast, changes
in telomere sequences resulting from altered telomerase RNA templates
cause a deregulation of telomere length and eventual cell death.
Thus, telomerase is a critical player in telomere maintenance.
In most human somatic cells, contrary to cells of the germline,
telomeres shorten with age, and telomerase is generally absent.
It has been proposed that telomere length may signal exit from
the cell cycle, and senescence. Many immortalized and tumour cells
have active telomerase leading to the proposal that one of the
requirements for immortalization, and possibly carcinogenesis,
may be the activation of telomerase. Recently it was demonstrated
that the expression of telomerase, in conjunction with alterations
in p53, Rb and Ras converts some primary cells into tumorigenic
cells. Moreover, inhibiting telomerase results in telomere loss,
chromosome damage, and cell death of various human cancer cell
lines, validating the search for telomerase inhibitors as anticancer
therapies.
Dr. Autexier’s research aims to establish a molecular
base for the development of anticancer therapies that target
telomerase or telomere integrity and the efficacious treatments
of age-related cell death. Studies in the lab are focused on
characterizing the mechanisms that regulate the telomerase ribonucleoprotein,
telomere length and cell viability, evaluating the principle
of anti-cancer treatments that target telomerase or telomere
integrity in combination with chemotherapeutics and identifying
and characterizing protective functions of telomerase in neuronal
and immortal human cells.
SOME RECENT PUBLICATIONS:
Shawi, M. and Autexier, C. 2007. Telomerase, senescence and aging. Mechanisms of Ageing and Development, in press doi: 10.1016/j.mad.2007.11.007
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
Fakhoury, J., Nimmo, G.A.M. and Autexier, C. 2007. Targeting cancer with telomerase immunotherapy. Anti-Cancer Agents in Medicinal Chemistry 7, 475-483.
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.
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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