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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 activity identified
Concern about gold G, cap P

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
Remove white arrow

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 Remove white arrow 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 Similar to slide 27, delete this one. Use same slide Hemann & Greider NAR 2000

24 Progressive telomere shortening during mTR+/- breeding
Similar to slide 27, delete this one. Use same slide

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
Similar to slide 27, delete this one. Use same slide

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
Similar to slide 27, delete this one. Use same slide

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
Switch order. Done. NEJM 357 p1317 (2007)

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

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

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


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