Carol Greider, Ph.D.Image

Daniel Nathans Professor and Director of Molecular Biology and Genetics

Professor of Oncology

Contact Information

Room 702, Preclinical Teaching Building
410-955-3482; 410-614-6506
410-614-2987 (Fax)
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Research Interests

Telomeres and telomerase in chromosome maintenance and stability

Telomeres are the functional elements on chromosome ends that protect the ends and distinguish them from DNA breaks. In the absence of a functional telomere, broken ends may signal DNA damage responses and may fuse together generating chromosome instability. Telomere DNA consists of many tandem repeats of a simple sequences such as the TTAGGG repeats on mammalian chromosome ends. The ends are synthesized and maintained by and the enzyme telomerase. Telomerase is a Ribonucleoprotein DNA polymerase that contains a catalytic protein subunit and an essential RNA component. The telomerase RNA provides the template for the TTAGGG repeats that are synthesized onto chromosome ends. In the absence of telomerase, telomeres shorten progressively and chromosome instability and ultimately cell death occurs. Although many somatic cells in humans do not express telomerase, over 90% of human tumors have telomerase activity. Work from our lab and others suggested that inhibition of telomerase may inhibit the growth of cancer cells. To understand the biology of telomeres and telomerase ,our lab is focused on both the details of telomerase biochemistry as well as the consequences of the loss of telomeres function. In early studies we extensively characterized the functional regions of the Tetrahymena telomerase RNA. We developed a reconstitution system in which we could assay the function of mutant RNAs. These studies mapped the essential RNA functional regions. In addition to continuing our studies on the Tetrahymena telomerase, we have recently determined the secondary structure of the human telomerase RNA component. Using phylogenetic analysis of 35 vertebrate telomerase RNAs, we identified four highly conserved domains in the RNA structure. We are currently analyzing the role of these regions in human and mouse telomerase.

To understand how telomere functions to provide chromosome stability and how telomerase might play a role in cancer, we generated a telomerase null mouse. Mice that lack the gene encoding the mouse Telomerase RNA (mTR) show progressive telomere shorting during successive breeding. The mice are viable for up to six generations although in the later generations there is severe reduction in fertility due to apoptosis in the germ cells. Crosses of these telomerase null mice to other tumor prone mouse models suggest that under some circumstances tumor formation can be greatly reduced when telomerase in absent. This suggests that telomerase inhibition may be a useful approach to cancer treatment. However in certain genetic backgrounds a reduction in tumor formation is not seen, likely due to the absence of pathways for cell death. These studies indicate that telomerase plays a role at multiple stages in tumorigenesis and may help narrow the choice of which cancers to target for telomerase inhibition. We are using the mTR-/- mice to understand the cellular events that occur when telomere function is lost. Evidence suggests that loss of telomere function may lead to a DNA damage checkpoint. We are testing this hypothesis and determining the cellular consequences of the loss of telomere function.

Selected Publications

  • Chen, J.-L., Blasco, M., and Greider, C.W. (2000). A Secondary structure of vertebrate telomerase RNA. Cell 100: 503-514.
  • Hemann, M. T., and Greider, C. W. (2000). Wild derived inbred mouse strains have short telomeres, Nucleic Acids Research 28: 4474-4478.
  • Chen, Q., IJpma, A., and Greider, C. W. (2001). Two survivor pathways that allow growth in the absence of telomerase are generated by distinct telomere recombination events. Mol Cell Biol 21: 1819-1827.
  • Hemann, M. T., Rudolph, L., Strong, M., DePinho, R. A., Chin, L., and Greider, C. W. (2001). Telomere dysfunction triggers developmentally regulated germ cell apoptosis. Mol. Biol. Cell. 12; 2023-2030.
  • Hackett, J., Feldser, D. and Greider, C. W. (2001). Telomere dysfunction increases mutation rate and genomic instability. Cell 106: 275-286.
  • 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.
  • Mason, D., Autexier, C., and Greider, C. W. (2001). Tetrahymena proteins p80 and p95 are not core telomerase components. Proc. Natl. Acad. Sci. USA 98; 12368-12373.
  • Chen, J.-L., Opperman, K. K., and Greider, C. W. (2002). A critical stem loop structure in the CR4-CR5 domain of mammalian telomerase RNA. Nucl. Acids Res. 30: 592-597.
  • Hathcock, K. S., Hemann, M. T., Opperman, K. K., Strong, S. A., Greider, C. W., and Hodes, R. J. (2002). Haploinsufficiency of mTR results in defects in telomere elongation. . Proc. Natl. Acad. Sci. USA 99; 3591-3596.
 
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