Dr. Carol Greider
The role of telomeres in genetic instability and cancer
Daniel Nathans Professor of Molecular Biology and Genetics
Professor of Oncology
Ph.D., Molecular Biology, University of California, Berkeley, CA
Fellow, Cold Spring Harbor Laboratory, NY
Telomeres are essential for chromosome maintenance. In the absence of
telomere function, chromosomes undergo end-to-end fusion and other rearrangements. The
maintenance of telomere length plays an important role in the growth of tumor
cells and in long term growth of stem cells. Telomere length is maintained by
the enzyme telomerase. Telomerase is a unique polymerase requiring both a
reverse transcriptase-like protein and an RNA component that synthesizes
telomere sequences onto chromosome ends. Telomerase is active in most tumors
and not active in many somatic cells, making it an interesting target for
anti-cancer therapy. In the absence of telomerase, telomeres shorten
progressively, and telomere function is lost after a number of cell
The Greider lab is interested in the structure and function of telomerase,
the cellular and organism consequences of the loss of telomere function. To probe
the role of telomeres in normal cells, stem cells and in tumors, the Greider
laboratory generated telomerase-null mice. With successive generation of
breeding these telomerase-null mice, telomeres shorten progressively. The
short telomeres in the late generation mice, trigger apoptosis or can
initiate chromosomal rearrangements. Thus the outcome of telomerase inhibition depends
on the genetic background of the cell. Since telomerase inhibition is being
pursued as an anticancer strategy, understanding the primary trigger for cell
death is in response to short telomeres is essential.
In the future, the Greider lab will focus on understanding the cellular
pathways of cell death in response to short telomeres in mouse and yeast
cells. They will further characterize the mechanisms that lead to chormosomal
rearrangments. They will investigate the signals and consequences of stem
cell loss when telomeres are short. Finally, they will identify new genes in the
pathway that responds to telomere dysfunction.
Hackett, J., & Greider, C. W. 2001. Telomere dysfunction increases mutation
rate and genomic instability. Cell. 106:275-286.
Hao, L. Y., Armanios, M., Strong, M. A., Karim, B. O., Feldser, D. M., Huso,
D. L., et al. 2005. Short telomeres, even in the presence of telomerase, limit
tissue renewal capacity. Cell. 123:1121-1131.
Hemann, M. T., Strong, M. A., Hao, L. Y., & Greider, C. W. 2001. The shortest
telomere, not average telomere length, is critical for cell viability and
chromosome stability. Cell. 107:66-77.
IJpma, A. S., & Greider, C. W. 2003. Short telomeres induce a DNA damage
response in Saccharomyces cerevisiae. Mol. Cell Biol. 14:987-1001.
Qi, L., Strong, M. A., Karim, B. O., Huso, D. L., & Greider, C. W. 2005.
Telomere fusion to chromosome breaks reduced oncogenic translocations and
tumor formation. Nat. Cell Biol. 7:706-711.