Telomere loss: mitotic clock or genetic time bomb?
The Holy Grail of gerontologists investigating cellular senescence is the mechanism responsible for the finite proliferative capacity of somatic cells. In 1973, Olovnikov proposed that cells lose a small amount of DNA following each round of replication due to the inability of DNA polymerase to fully replicate chromosome ends (telomeres) and that eventually a critical deletion causes cell death. Recent observations showing that telomeres of human somatic cells act as a mitotic clock, shortening with age both in vitro and in vivo in a replication dependent manner, support this theory's premise. In addition, since telomeres stabilize chromosome ends against recombination, their loss could explain the increased frequency of dicentric chromosomes observed in late passage (senescent) fibroblasts and provide a checkpoint for regulated cell cycle exit. Sperm telomeres are longer than somatic telomeres and are maintained with age, suggesting that germ line cells may express telomerase, the ribonucleoprotein enzyme known to maintain telomere length in immortal unicellular eukaryotes. As predicted, telomerase activity has been found in immortal, transformed human cells and tumour cell lines, but not in normal somatic cells. Telomerase activation may be a late, obligate event in immortalization since many transformed cells and tumour tissues have critically short telomeres. Thus, telomere length and telomerase activity appear to be markers of the replicative history and proliferative potential of cells; the intriguing possibility remains that telomere loss is a genetic time bomb and hence causally involved in cell senescence and immortalization.
Harley
C B
CB
Department of Biochemistry, McMaster University, Hamilton, Ont., Canada.
D000818:Animals; D002455:Cell Division; D002461:Cell Line, Transformed / Q000166:cytology; D016922:Cellular Senescence / Q000502:physiology*; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D004261:DNA Replication; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008938:Mitosis; D016615:Telomere / Q000502:physiology*
D004253:DNA Nucleotidylexotransferase