Role of oxidative stress in telomere shortening in cultured fibroblasts from normal individuals and patients with ataxia-telangiectasia.
Cells from patients with the autosomal recessive disorder ataxia-telangiectasia (A-T) display accelerated telomere shortening upon culture in vitro. It has been suggested that A-T cells are in a chronic state of oxidative stress, which could contribute to their enhanced telomere shortening. In order to examine this hypothesis, we monitored the changes in telomere length in A-T homozygous, heterozygous and control fibroblasts cultured in vitro under various conditions of oxidative stress using quantitative fluorescent in situ hybridization. Compared with normal cells, the rate of telomere shortening was 1.5-fold increased under 'normal' levels of oxidative stress in A-T heterozygous cells and 2.4-3.2-fold in A-T homozygous cells. Mild chronic oxidative stress induced by hydrogen peroxide increased the rate of telomere shortening in A-T cells but not in normal fibroblasts and the telomere shortening rate decreased in both normal and A-T fibroblasts if cultures were supplemented with the anti-oxidant phenyl-butyl-nitrone. Increased telomere shortening upon oxidative stress in A-T cells was associated with a significant increase in the number of extra-chromosomal fragments of telomeric DNA and chromosome ends without detectable telomere repeats. We propose that the ATM (A-T mutated) protein has a role in the prevention or repair of oxidative damage to telomeric DNA and that enhanced sensitivity of telomeric DNA to oxidative damage in A-T cells results in accelerated telomere shortening and chromosomal instability.
Tchirkov
Andrei
A
The Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada V5Z 1L3.
Lansdorp
Peter M
PM
D000293:Adolescent; D001260:Ataxia Telangiectasia / Q000378:metabolism*; D002648:Child; D019457:Chromosome Breakage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology*; D016615:Telomere / Q000378:metabolism*
D006861:Hydrogen Peroxide