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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 of Molecular Biology and Genetics Johns Hopkins University School of Medicine.

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slide1

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

slide2

Telomeres and Telomerase: Bridging Science and Society

  • Curiosity driven research establishes fundamental knowledge that fuels
  • practical applications.
telomeres are the ends of chromosomes
Telomeres are the ends of chromosomes
  • Protect ends
  • Maintain length
tetrahymena thermophila single celled animal with 40 000 chromosomes
Tetrahymena thermophila: single celled animal with 40,000 chromosomes

Elizabeth Blackburn & Joe Gall (1978):

Defined telomere sequence as tandem repeats of TTGGGG

telomeres shorten as cells divide
Telomeres shorten as cells divide

TTGGGG

Replication

Replication

Replication

why does telomerase matter
Why does telomerase matter?

It is required for cells that must divide many times

Cancer

Tissue renewal

telomeres shorten with age
Telomeres shorten with age

Telomerase is limiting in cells

Vaziri et al. AJHG (1995)

telomerase knockout mouse
Telomerase knockout mouse

Blasco et al. Cell 1997

slide18

Telomere shortening leads to cell death

Replication

Replication

Replication

Cell Death

dyskeratosis congentia causes bone marrow failure
Dyskeratosis congentia causes bone marrow failure
  • Skin and nail problems
    • Skin hyperpigmentation
    • Rashes
    • Abnormal nail growth
  • Mortality
    • Bone marrow failure
    • Cancer
    • other?
tert mutations cause autosomal dominant inheritance of dyskeratosis congentia
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)

cast ei mice have short telomeres similar to humans
Cast/Ei mice have short telomeres similar to humans
  • Bred mTR null allele onto Cast/Ei background

Hemann & Greider NAR 2000

short telomeres in cast eij mtr mice
Short telomeres in CAST/EiJ mTR+/- mice

Telomerase is limiting in cells

Hao et al. Cell 2005

decreased survival of mtr from later generation heterozygous crosses
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

short telomeres in wt5 mice
Short telomeres in Wt5* mice

Hao et al. Cell 2005

short telomeres cause phenotypes in wt mice
Short telomeres cause phenotypes in Wt* mice

TESTIS APOPTOSIS

SPLEEN WEIGHT

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

wt mice reestablish telomere equilibrium after several generations
Wt* mice reestablish telomere equilibrium after several generations

Telomerase is limiting in cells

Armanios et al. AJHG 2009

reestablishment of telomere length equilibrium rescues testes phenotype
Reestablishment of telomere length equilibrium rescues testes phenotype

Armanios et al. AJHG (2009)

short telomeres in lung disease
Short telomeres in lung disease

NEJM 357 p1317 (2007)

many diseases seen in families with insufficient telomerase share features of age related disease
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
slide38
Bridging Science and Society: Understanding of telomeres came from curiosity about chromosome maintenance
slide39

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

greider lab
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

telomere length predicts mortality rate
Telomere length predicts mortality rate

Cawthon et al. Lancet (2005)