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Telomerase

Telomerase. Mallory Demonch Biol 455 March 24, 2008. 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. Telomere function-life span regulation and chromosomal integrity.

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Telomerase

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  1. 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 http://en.wikipedia.org/wiki/Telomere

  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 http://en.wikipedia.org/wiki/File:Tetrahymena_thermophila.png

  6. http://en.wikipedia.org/wiki/Telomerase

  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 http://en.wikipedia.org/wiki/File:Telomerase_illustration.jpg

  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 • 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 http://en.wikipedia.org/wiki/File:HeLa_Hoechst_33258.jpg

  11. Telomerase and possible causes to its activity in cancer • p53 inactivation • C-myc expression • Steroid hormones www.biocarta.com/pathfiles/h_tertPathway.gif

  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. 2002. Immunosenescence phenotypes in the telomerase knockout mouse. Springer Semin Immunopathol 24:75–85. • Cong, Y., W.E. Wright, and J.W. Shay. 2002. Human Telomerase and Its Regulation. Microbiology and Molecular Biology Reviews 66: 407-425. • Cristofari, G. and J. Lingner. 2006. Telomere length homeostasis requires that telomerase levels are limiting. EMBO Journal 25: 565-574. • Flores I. et al, 2006. Genetic analysis of Myc and Telomerase Interactions in Vivo. Molecular and Cellular Biology 26: 6130-6138. • Hahn, W.C. 2003. Role of Telomeres and Telomerase in the Pathogenesis of Human Cancer. Journal of Clinical Oncology 21: 2034-2043. • Yuan, X. et al. 1999.Presence of telomeric G-strand tails in the telomerase catalytic subunit TERT knockout mice. Genes to Cells 4: p563-572.

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