1. Mallory Demonch Biol 455 March 24, 2008
Telomerase
Mallory Demonch
Biol 455
March 24, 2008

2. What is a Telomere? Ends of Chromosomes
Repeated DNA and specific DNA-binding proteins (TRF1 and TRF2).
5’-TTAGGG-3’ repeats
T-loop
M.A. Blasco, 2002

3. Telomere function-life span regulation and chromosomal integrity
Telomere shortening
End Replication Problem
Telomeres get shorter at each replication

4. Hayflick Limit and Crisis
William C. Hahn, 2003

5. Telomerase- RNA-dependent DNA polymerase
-elongates and maintains telomeres
-1st discovered in 1985 in Tetrahymena

7. Telomerase subunits-hTERC (hTR) and hTERT
hTERC-RNA template 3'-CAAUCCCAAUC-5'
Ubiquitously expressed in mammalian cells
hTERT-catalytic component
Reverse transcriptase
Rate-limiting
component
of telomerase

8. Knockout Mice Experiments
TR -/- : Viable for only 4 to 6 generations, accumulate chromosome fusions and telomeres shorten after each generation
partial embryonic mortality due to mutations and reduced activity in highly proliferative tissues
TERT -/-: Viable and 2nd generation had same phenotypes to the 1st generation
Also fertile
Not required for embryogenesis
X Yuan, et al. 1999

9. Telomerase and Cancer Normal Cells Cancer Cells
little to no Telomerase activity
Limited life span
Exception: highly proliferative tissues
Cancer Cells
High telomerase Activity
Immortalized
X Yuan, et al. 1999

10. Telomerase sufficient to immortalize cells
hTERT activation saves cells from replicative senescence and crisis
Also cooperates with other oncogenes and tumor suppressors
HeLa Cells-high telomerase activity

11. Telomerase and possible causes to its activity in cancer
p53 inactivation
C-myc expression
Steroid hormones

12. Summary
Telomeres limit cell life span, which prevents tumorigenesis by preventing accumulation of oncogenic mutations
Telomerase elongate telomeres and is sufficient to rescue cells from Hayflick and Crisis leading to “immortal” cells.
Telomerase cooperates with other oncogenes and tumor suppressors to induce tumorigenesis
Telomerase activity is repressed in normal cells and up regulated in cancer cells.

13. References
Blasco, M.A Immunosenescence phenotypes in the telomerase knockout mouse. Springer Semin Immunopathol 24:75–85.
Cong, Y., W.E. Wright, and J.W. Shay Human Telomerase and Its Regulation. Microbiology and Molecular Biology Reviews 66:
Cristofari, G. and J. Lingner Telomere length homeostasis requires that telomerase levels are limiting. EMBO Journal 25:
Flores I. et al, Genetic analysis of Myc and Telomerase Interactions in Vivo. Molecular and Cellular Biology 26:
Hahn, W.C Role of Telomeres and Telomerase in the Pathogenesis of Human Cancer. Journal of Clinical Oncology 21:
Yuan, X. et al Presence of telomeric G-strand tails in the telomerase catalytic subunit TERT knockout mice. Genes to Cells 4: p