Primary fibroblasts and other primary, untransformed cell types can undertake only a limited number of cell doublings in vitro. The number of doublings is correlated with the age of the donor of the cells, and also with the lifespan of the donor species. It is possible that this in vitro limit on cell doublings is the cause of organismal aging; however, the cause of the limit on total cell doublings is entirely unknown. We have recently discovered that as human fibroblasts age, their chromosomal telomeres get shorter and shorter, with no apparent limit to this shortening. It is possible that some chromosome ends lose all of their functional telomeric sequences, and it is this loss that causes the permanent cell cycle exit of senescent cells. Thus, telomere loss could be the ultimate cause aging. We plan to examine the structure and loss of mammalian telomeres with aging, to investigate the mechanism of telomere maintenance in germ cells and immortal cells, to isolate and characterize human telomerase (the enzyme responsible for telomere maintenance), and to try and see whether there is a cause-and-effect relationship between telomere loss and aging. Whether or not telomere loss is a cause of cellular senescence, the experiments proposed will provide valuable information on the structure and maintenance of human telomeres.
| Tom, Hui-I Kao; Greider, Carol W (2010) A sequence-dependent exonuclease activity from Tetrahymena thermophila. BMC Biochem 11:45 |
| Chen, Jiunn-Liang; Greider, Carol W (2005) Functional analysis of the pseudoknot structure in human telomerase RNA. Proc Natl Acad Sci U S A 102:8080-5; discussion 8077-9 |
| Chen, Jiunn-Liang; Greider, Carol W (2003) Determinants in mammalian telomerase RNA that mediate enzyme processivity and cross-species incompatibility. EMBO J 22:304-14 |
| Chen, Jiunn-Liang; Greider, Carol W (2003) Template boundary definition in mammalian telomerase. Genes Dev 17:2747-52 |
| Chen, Jiunn-Liang; Opperman, Kay Keyer; Greider, Carol W (2002) A critical stem-loop structure in the CR4-CR5 domain of mammalian telomerase RNA. Nucleic Acids Res 30:592-7 |
| Le, S; Sternglanz, R; Greider, C W (2000) Identification of two RNA-binding proteins associated with human telomerase RNA. Mol Biol Cell 11:999-1010 |
| Greider, C W (1998) Telomerase activity, cell proliferation, and cancer. Proc Natl Acad Sci U S A 95:90-2 |
| Le, S; Zhu, J J; Anthony, D C et al. (1998) Telomerase activity in human gliomas. Neurosurgery 42:1120-4;discussion 1124-5 |
| Blasco, M A; Lee, H W; Hande, M P et al. (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91:25-34 |
| Greider, C W (1996) Telomere length regulation. Annu Rev Biochem 65:337-65 |
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