Telomeres and Telomerase in Can Brief Biography D r. Greider’s holds a bachelor’s degree in biology from the University of California, Santa Barbara, and a doctorate in molecular biology from UC Berkeley. Her postgraduate training began in 1988 as a fellow at the Cold Spring Harbor Laboratory on Long Island, where she progressed to the rank of investigator before joining Johns Hopkins in 1997 as an associate professor in the Department of Mo- lecular Biology and Genetics. She was promoted to full professor in 1999 and holds a joint appointment in the Department of Oncology. She served as interim director of the Molecular Biology was named Director of Molecular Biology in August 2003. Her career has focused on investigating basic biological questions, but the answers have turned out to have dramatic implications for disease research. As a University of California at Berkeley graduate student studying how a single-celled, pond-dwelling critter copied its chromosomes, Greider discovered the enzyme, called telomerase, that rebuilds chromosomes’ ends. Now, years later, telomerase is recognized as a major player in cancers and is a possible target for treating them. Monday, September 19, 2005 4:30 pm, Deans Auditorium Department of Molecular Biology and Genetics, Department of Oncology and The Johns Hopkins University School of Medicine ncer and Stem Cell Failure C ancer is characterized by frequent chromosomal rearrangements. Telomeres, the ends of chromosomes consist of many tandem repeats of the sequence TTAGGG and are required for stable chromosome maintenance. The enzyme telomerase maintains telomeres by repeatedly adding telomeric repeats onto chromosome ends at each cell division. Telomerase activity is not present in many normal tissues but is re-activated in many tumors. Since telomere shortening leads to cell death or arrest, telomerase is a target for cancer chemotherapy. We are interested in the mechanism that lead to cell death when telomeres are short. We have used a telomerase knockout mTR-/- mouse to disect the role of telomere shortening in tumorigenesis. In these mice we found that the shortest telomere in the telomere length distribution triggers apoptosis (1). The ATM and ATR protein kinases, which are involved in DNA damage response, are also involved in telomere function. Using Atm-/- mTR-/- double null mice, we found that loss of ATM destabilizes short telomeres and increases apoptosis in response to telomere shortening (2). Telomere dysfunction in Atm-/- mTR-/- increases the survival of these mice by two different mechanisms (3). Further evidence for telomere shortening in the presence of telomerase comes from the inherited disease autosomal dominant dyskeratosis congenita (AD DC), which is caused by mutations in telomerase RNA or protein components. AD DC may be one manifestation of a syndrome of telomere shortening that limits stem cell proliferation and causes human disease. We have recently developed a mouse model that mimics AD DC. We found that haploinsuffiency for telomerase RNA causes telomere shortening, infertility and bone marrow abnormalities that indicate stem cell failure. To our surprise, wildtype animals that inherited short telomeres also showed evidence of stem cell failure. Thus, short telomeres can cause disease even in the presence of wildtype levels of telomerase. This finding has implications for both AD DC families as well as normal individuals who inherit short telomeres. References: 1. Hemann et al. Cell, 2001. 107: p. 67-77. 2. Qi et al., Cancer Res, 2003. 63 (23): p. 8188-8196. 3. Qi et al Nature Cell Biol. 7, (2005) p706 – 711.

Telomeres and Telomerase in Cancer and Stem Cell Failure · Brief Biography D r. Greider’s holds a bachelor’s degree in biology from the University of California, Santa Barbara,

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Telomeres and Telomerase in Can

Brief Biography

D r. Greider’s holds a bachelor’s degree in biology from the University of California, Santa Barbara, and a doctorate in

molecular biology from UC Berkeley. Her postgraduate training began in 1988 as a fellow at the Cold Spring Harbor Laboratory on Long Island, where she progressed to the rank of investigator before joining Johns Hopkins in 1997 as an associate professor in the Department of Mo-lecular Biology and Genetics. She was promoted to full professor in 1999 and holds a joint appointment in the Department of Oncology. She served as interim director of the Molecular Biology was named Director of Molecular Biology in August 2003.

Her career has focused on investigating basic biological questions, but the answers have turned out to have dramatic implications for disease research. As a University of California at Berkeley graduate student studying how a single-celled, pond-dwelling critter copied its chromosomes, Greider discovered the enzyme, called telomerase, that rebuilds chromosomes’ ends. Now, years later, telomerase is recognized as a major player in cancers and is a possible target for treating them.

Monday, September 19, 2005 4:30 pm, Deans Auditorium

Department of Molecular Biology and Genetics, Department of Oncology and The Johns Hopkins University School of Medicine

ncer and Stem Cell Failure

C ancer is characterized by frequent chromosomal rearrangements. Telomeres, the ends of chromosomes consist of many tandem repeats of

the sequence TTAGGG and are required for stable chromosome maintenance. The enzyme telomerase maintains telomeres by repeatedly adding telomeric repeats onto chromosome ends at each cell division. Telomerase activity is not present in many normal tissues but is re-activated in many tumors. Since telomere shortening leads to cell death or arrest, telomerase is a target for cancer chemotherapy. We are interested in the mechanism that lead to cell death when telomeres are short. We have used a telomerase knockout mTR-/- mouse to disect the role of telomere shortening in tumorigenesis. In these mice we found that the shortest telomere in the telomere length distribution triggers apoptosis (1). The ATM and ATR protein kinases, which are involved in DNA damage response, are also involved in telomere function. Using Atm-/- mTR-/- double null mice, we found that loss of ATM destabilizes short telomeres and increases apoptosis in response to telomere shortening (2). Telomere dysfunction in Atm-/- mTR-/- increases the survival of these mice by two different mechanisms (3).

Further evidence for telomere shortening in the presence of telomerase comes from the inherited disease autosomal dominant dyskeratosis congenita (AD DC), which is caused by mutations in telomerase RNA or protein components. AD DC may be one manifestation of a syndrome of telomere shortening that limits stem cell proliferation and causes human disease. We have recently developed a mouse model that mimics AD DC.

We found that haploinsuffiency for telomerase RNA causes telomere shortening, infertility and bone marrow abnormalities that indicate stem cell failure. To our surprise, wildtype animals that inherited short telomeres also showed evidence of stem cell failure. Thus, short telomeres can cause disease even in the presence of wildtype levels of telomerase. This finding has implications for both AD DC families as well as normal individuals who inherit short telomeres.

References: 1. Hemann et al. Cell, 2001. 107: p. 67-77. 2. Qi et al., Cancer Res, 2003. 63 (23): p. 8188-8196. 3. Qi et al Nature Cell Biol. 7, (2005) p706 – 711.