Carol Greider, Ph.D.
Daniel Nathans Professor and Director of Molecular Biology and Genetics
Preclinical Teaching Building Room 603
Telomeres and telomerase in chromosome maintenance and stability
Telomeres protect chromosome ends from being recognized as DNA damage and chromosomal rearrangements. Conventional replication leads to telomere shortening, but telomere length is maintained by the enzyme telomerase that synthesizes telomere sequences de novo onto chromosome ends. Telomerase is specialized reverse transcriptase, requiring both a catalytic protein and an essential RNA component. In the absence of telomerase, telomeres shorten progressively as cells divide, and telomere function is lost. For this reason, telomerase is required for cells that undergo many rounds of divisions, especially tumor cells and some stem cells. My lab is focused understanding telomerase and cellular and organismal consequences of telomere dysfunction. We use biochemistry, yeast and mice to examine telomere function. We generated telomerase null mice that are viable and show progressive telomere shortening for up to six generations. In the later generations, when telomeres are short, cells die via apoptosis or senescence. Crosses of these telomerase null mice to other tumor prone mice show that tumor formation can be greatly reduced by short telomeres. We also are using our telomerase null mice to explore the essential role of telomerase stem cell viability. Telomerase mutations cause autosomal dominant dyskeratosis congenita. People with this disease die of bone marrow failure, likely due to the stem cell loss. We have developed a mouse model to study this disease. Future work in the lab will focus on identifying genes that induce DNA damage in response to short telomeres, identifying how telomeres are processed and how telomere elongation is regulated.
Strong, M.A.,Vidal-Cardenas, S.L., Karim, B., Yu, H., Guo, N., Greider, C.W., (2011). Phenotypes in mTERT+/- and mTERT-/- Mice are Due to Short Telomeres, Not Telomere-Independent Functions of TERT. Mol Cell Biol. 31: 2369-2379.
Craig, N.L., Cohen-Fix, O., Green, R., Greider, C.W., Storz, G., and Wolberger, W. (2010). Molecular Biology: Principles of Genome Function (Oxford, Oxford University Press).
Tom, H.I., and Greider, C.W. (2010). A Sequence-Dependent Exonuclease Activity From Tetrahymena thermophila; BMC Biochem. 11:45.
Vidal-Cardenas, S.L., and Greider, C.W. (2010). Comparing effects of mTR and mTERT deletion on gene express and DNA damage response: a critical examination of telomere length maintenance-independent roles of telomerase. Nucleic Acids Res. 38: 60-71.
Armanios, M., Alder, J.K., Parry, E.M., Karim, B., Strong, M.A., and Greider, C.W. (2009). Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet 85, 823-832.
Ma, Y., and Greider, C.W. (2009). Kinase-Independent functions of TELI in telomere maintenance. Mol. Cell Biol. 5193-5202.
Morrish T.A., Greider C.W. (2009). Short telomeres initiate telomere recombination in primary and tumor cells. PLoS Genet. 5, e1000357.
Feldser, D., and Greider, C.W. (2007). Short telomeres limit tumor progression in vivo by inducing senescence. Cancer Cell: 11, 461-469.
Frank, C. J., Hyde, M., and Greider, C.W. (2006). Regulation of telomere elongation by the cyclin-dependent kinase CDK1. Mol Cell: 24, 423-432.
Hao, L. Y., Armanios, M., Strong, M. A., Karim, B., Feldser, D. M., Huso, D., and Greider, C.W. (2005). Short Telomeres, even in the Presence of Telomerase, Limit Tissue Renewal Capacity. Cell 123: 1121-1131.
IJpma, A., and Greider, C.W. (2003). Short telomeres induce a DNA damage response in S. cerevisiae. Mol. Biol. Cell 14: 987-1001.
Hemann, M. T., Strong, M., Hao, L.-Y., and Greider, C.W. (2001). The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107: 66-77.
Hackett, J., Feldser, D.M., and Greider, C.W. (2001). Telomere dysfunction increases mutation rate and genomic instability. Cell 106: 275-286.
Chen, J.-L., Blasco, M., and Greider, C.W. (2000). A Secondary structure of vertebrate telomerase RNA. Cell 100: 503-514.
Blasco, M.A., Lee, H.-W., Hande, P.M., Samper, E., Lansdorp, P.M., DePinho, R.A., and Greider, C.W. (1997). Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91: 25-34.
Autexier, C., and Greider, C.W. (1995). Boundary elements of the Tetrahymena telomerase RNA template and alignment domains. Genes & Dev. 9: 2227-2239.
Harley, C.B., Futcher, A.B., and Greider, C.W. (1990). Telomeres shorten during ageing of human fibroblasts. Nature 345: 458–460.
Greider, C.W., and Blackburn, E.H. (1989). A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337: 331–337.
Greider, C.W., and Blackburn, E.H. (1985). Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43: 405–413.