Life span determination in normal human cells may be regulated by nucleoprotein structures called telomeres, the physical ends of eukaryotic chromosomes. Telomeres have been shown to be essential for chromosome stability and function and to shorten with each cell division in normal human cells in culture and with age in vivo. Reversal of telomere shortening by the forced expression of telomerase in normal cells has been shown to elongate telomeres and extend the replicative life span (H. Vaziri and S. Benchimol, Curr. Biol. 8:279-282, 1998; A. G. Bodnar et al., Science 279:349-352, 1998). Extension of the life span as a consequence of the functional inactivation of p53 is frequently associated with loss of genomic stability. Analysis of telomerase-induced extended-life-span fibroblast (TIELF) cells by G banding and spectral karyotyping indicated that forced extension of the life span by telomerase led to the transient formation of aberrant structures, which were subsequently resolved in higher passages. However, the p53-dependent G1 checkpoint was intact as assessed by functional activation of p53 protein in response to ionizing radiation and subsequent p53-mediated induction of p21(Waf1/Cip1/Sdi1). TIELF cells were not tumorigenic and had a normal DNA strand break rejoining activity and normal radiosensitivity in response to ionizing radiation.
Both the xrs and V-3 lines of Chinese hamster ovary cells exhibit marked sensitivity to ionizing radiation. They are also sensitive to agents such as bleomycin and H2O2 but exhibit normal responses to ultraviolet light and mitomycin C. Both cell lines are defective in split-dose repair and repair of double-strand breaks in DNA. Analysis of response to radiation as a function of age in the cell cycle indicates that both cell lines exhibit a marked sensitivity in late G1 and early S phase with more limited sensitization throughout the remainder of the cell cycle.
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