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Telomerase and the consequence of telomere dysfunction

Telomerase and the consequence of telomere dysfunction. AAAS Annual meeting February 19 th 2010. Carol Greider Daniel Nathans Professor & Director Department of Molecular Biology and Genetics Johns Hopkins University School of Medicine.

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Telomerase and the consequence of telomere dysfunction

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  1. Telomerase and the consequence of telomere dysfunction AAAS Annual meeting February 19th 2010 Carol Greider Daniel Nathans Professor & Director Department of Molecular Biology and Genetics Johns Hopkins University School of Medicine

  2. Telomeres and Telomerase: Bridging Science and Society • Curiosity driven research establishes fundamental knowledge that fuels • practical applications.

  3. Telomeres are the ends of chromosomes • Protect ends • Maintain length

  4. Tetrahymena thermophila: single celled animal with 40,000 chromosomes Elizabeth Blackburn & Joe Gall (1978): Defined telomere sequence as tandem repeats of TTGGGG

  5. Telomeres shorten as cells divide TTGGGG Replication Replication Replication

  6. Tetrahymena and yeast: conservation of telomere function & telomere elongation Nature July 1984

  7. Telomerase activityidentified

  8. Telomerase allows telomere length equilibrium maintenance TR Replication Telomerase TERT

  9. Why does telomerase matter? It is required for cells that must divide many times Cancer Tissue renewal

  10. Telomere shortening in cellular senescence Nature May 1990

  11. Telomeres shorten with age Telomerase is limiting in cells Vaziri et al. AJHG (1995)

  12. Using laboratory mice to probe telomere function

  13. Telomerase knockout mouse Blasco et al. Cell 1997

  14. Quantitative analysis of telomere length

  15. Telomeres shorten progressively in telomerase-null mice Blasco et al. Cell 1997

  16. Loss of telomere sequence leads to loss of telomere function WT KO-G2 KO-G4 KO-G6

  17. The consequences of short telomeres

  18. Telomere shortening leads to cell death Replication Replication Replication Cell Death

  19. Short telomeres limit cell growth Cancer Tissue renewal

  20. Nature 2001

  21. Dyskeratosis congentia causes bone marrow failure • Skin and nail problems • Skin hyperpigmentation • Rashes • Abnormal nail growth • Mortality • Bone marrow failure • Cancer • other?

  22. TERT mutations cause autosomal dominant inheritance of dyskeratosis congentia Hopkins Family 1 • Genetic anticipation. • Affected people are heterozygous for hTR or hTERT mutations. • Dominant negative or haploinsufficiency? Armanios et al. PNAS (2005)

  23. Cast/Ei mice have short telomeres similar to humans • Bred mTR null allele onto Cast/Ei background Hemann & Greider NAR 2000

  24. Progressive telomere shortening during mTR+/- breeding

  25. Short telomeres in CAST/EiJ mTR+/- mice Telomerase is limiting in cells Hao et al. Cell 2005

  26. Telomere shortening at each mTR+/- generation affects survival of offspring

  27. Decreased survival of mTR-/- from later generation heterozygous crosses Inheritance of short telomeres decreases survival. Resembles genetic anticipation in dyskeratosis congenita. Armanios et al. AJHG 2009

  28. Telomere shortening during mTR+/- breeding affects wildtype offspring

  29. Short telomeres in Wt5* mice Hao et al. Cell 2005

  30. Short telomeres cause phenotypes in Wt* mice TESTIS APOPTOSIS SPLEEN WEIGHT Genetic disease in the absence of telomerase mutation (Occult genetic disease)

  31. Wt* mice reestablish telomere equilibrium after several generations Telomerase is limiting in cells Armanios et al. AJHG 2009

  32. Reestablishment of telomere length equilibrium rescues testes phenotype Armanios et al. AJHG (2009)

  33. Telomere shortening implicated in several diseases Hopkins Family 1

  34. Short telomeres in lung disease NEJM 357 p1317 (2007)

  35. Many diseases seen in families with insufficient telomerase share features of age-related disease • Bone marrow failure • Immune senescence • Chemotherapy intolerance • Pulmonary fibrosis • Liver disease • Increased cancer incidence

  36. Syndromes of telomere shortening:the tip of the iceberg

  37. Wide distribution of telomere length in the human population Valdes et al, 2005 Lancet (2005)

  38. Bridging Science and Society: Understanding of telomeres came from curiosity about chromosome maintenance

  39. Summary and implications • Telomeres are required for chromosome end protection. • Telomerase is essential for telomere maintenance. • Telomere shortening leads to cell death or senescence after many cell divisions. • Short telomeres limit tissue renewal. • Telomere length may predict onset of certain age related diseases. Fundamental discoveries lead to clinical applications

  40. Greider Lab Collaborators Telomere length regulation Oncology Vinny Raganathan Mary Armanios Sofia Vidal-Cardenas Jonathan Alder Carla Connely Erin Parry Response to telomere dysfunction Pathology Nini Guo Baktiar Karim David Huso Margaret Strong Tammy Morrish

  41. New discoveries come from unlikely places

  42. Telomere length predicts mortality rate Cawthon et al. Lancet (2005)

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