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Telomerase and the consequence of telomere dysfunction AAAS Annual meeting February 19 th 2010 Carol Greider Daniel Nathans Professor & Director Department.

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Presentation on theme: "Telomerase and the consequence of telomere dysfunction AAAS Annual meeting February 19 th 2010 Carol Greider Daniel Nathans Professor & Director Department."— Presentation transcript:

1 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

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 Replication TTGGGG

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

7 Telomerase activity identified

8 Replication Telomerase allows telomere length equilibrium maintenance Telomerase TR TERT

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

10 Nature May 1990 Telomere shortening in cellular senescence

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

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 WTKO-G2 KO-G4KO-G6

17 The consequences of short telomeres

18 Telomere shortening leads to cell death Cell Death Replication

19 Short telomeres limit cell growth CancerTissue renewal

20 Nature 2001

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

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

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

24 Progressive telomere shortening during mTR+/- breeding

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

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 APOPTOSISSPLEEN WEIGHT Genetic disease in the absence of telomerase mutation (Occult genetic disease)

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

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 NEJM 357 p1317 (2007) Short telomeres in lung disease

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

41 New discoveries come from unlikely places

42

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


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