Telomerase

Mallory DemonchBiol 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/Telomerehttp://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.pnghttp://en.wikipedia.org/wiki/File:Tetrahymena_thermophila.png

http://en.wikipedia.org/wiki/Telomerasehttp://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.jpghttp://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. 1999X Yuan, et al. 1999

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. 1999X 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.jpghttp://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 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.