Mallory Demonch Biol 455 March 24, 2008 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 Telomere shortening End Replication Problem Telomeres get shorter at each replication http://en.wikipedia.org/wiki/Telomere

Hayflick Limit and Crisis William C. Hahn, 2003

Telomerase- RNA-dependent DNA polymerase -elongates and maintains telomeres -1st discovered in 1985 in Tetrahymena http://en.wikipedia.org/wiki/File:Tetrahymena_thermophila.png

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

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

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

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

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

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

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.

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.