Telomerase and the consequence of telomere dysfunction AAAS

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

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

Telomeres are the ends of chromosomes § Protect ends § Maintain length

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 TTGGGG Replication

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

Telomerase activity identified

Telomerase allows telomere length equilibrium maintenance TR Replication Telomerase TERT

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

Telomere shortening in cellular senescence Nature May 1990

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

Using laboratory mice to probe telomere function

Telomerase knockout mouse Blasco et al. Cell 1997

Quantitative analysis of telomere length

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

Loss of telomere sequence leads to loss of telomere function WT KO-G 2 KO-G 4 KO-G 6

The consequences of short telomeres

Telomere shortening leads to cell death Replication Cell Death

Short telomeres limit cell growth Cancer Tissue renewal

Nature 2001

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 Hopkins Family 1 § Genetic anticipation. § Affected people are heterozygous for h. TR or h. TERT mutations. § Dominant negative or haploinsufficiency? Armanios et al. PNAS (2005)

Cast/Ei mice have short telomeres similar to humans § Bred m. TR null allele onto Cast/Ei background Hemann & Greider NAR 2000

Progressive telomere shortening during m. TR+/- breeding

Short telomeres in CAST/Ei. J m. TR+/- mice Telomerase is limiting in cells Hao et al. Cell 2005

Telomere shortening at each m. TR+/generation affects survival of offspring

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

Telomere shortening during m. TR+/breeding affects wildtype offspring

Short telomeres in Wt 5* mice Hao et al. Cell 2005

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 Telomerase is limiting in cells Armanios et al. AJHG 2009

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

Telomere shortening implicated in several diseases Hopkins Family 1

Short telomeres in lung disease NEJM 357 p 1317 (2007)

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

Syndromes of telomere shortening: the tip of the iceberg

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

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

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

§ New discoveries come from unlikely places

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