Carol Greider, Ph.D.
Our lab is interested in telomere function, chromosome stability and the biochemistry of telomerase. Telomeres are essential for both chromosome stability and for chromosome end replication. Telomerase is a ribonucleoprotein reverse transcriptase that synthesizes telomere repeats onto chromosome ends. Telomerase is required for telomerase length maintenance: in the absence of telomerase, telomeres shorten progressively. To understand human telomerase function, we established the secondary structure of the telomerase RNA component and identified four highly conserved functional domains in the RNA. Two of these domains the pesudoknot and CR4 region are essential for telomerase activity in vitro and two, the ScaRNA domain and CR7 are required for RNP assembly and stability in vivo. Mutations in these functional domains of the RNA are associated with the autosomal dominant human disease dyskeratosis congenita. This disease results in bone marrow failure due to the inability of stem cells to renew when telomeres become critically short. We are currently studying a mouse model of this disease.
Loss of telomerase results in chromosome instability that can lead to cancer. In addition, telomerase is activated in many human cancers. To disect the role of telomerase in cancer, we generated a telomerase-null mouse. These mice 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 is reduced while in others it is increased. We attribute the increase to an increase in genomic instability that fuels tumor initiation. We tested directly whether the absence of telomerase increases genetic instability by examining the mutation rate in the absence of telomerase in yeast. We found an increase in terminal deletions and the structure of chromosomes resembled the non-reciprocal translocations that are frequently found in human tumors. The chromosomal instability in these yeast cells was initiated by the loss of end protection exonucleolytic degradation of the telomeres. Normally telomeres protect chromosome ends from recognition as a double stranded DNA end. The loss of telomere function however, induced a DNA damage response similar to the response induced by DNA breaks. We are studying how the response to short telomeres differs from the well characterized DNA damage response using both yeast and mouse cells.
- 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, 67-77
- Hackett, J. and Greider C.W. (2003). End resection initiates genomic instability in the absence of telomerase. Mol. Biol Cell 23: 8450-8461.
- Chen, J.-L., and Greider, C.W. (2003) Template boundary definition in mammalian telomerase. Genes Dev. 17: 2747-2752.
- Qi, L., Strong, M., Karim, B. O., Huso, D. L., and Greider, C. W. (2003). Short telomeres and loss of ATM synergistically increase telomere dysfunction and suppress tumorigenesis. Cancer Research 63: 8188-8196.
- Chen, J.L., and Greider, C.W. (2004). Telomerase RNA structure and function: implications for dyskeratosis congentia Trends Biochem Sci. 29, 183-192.