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Human Molecular Genetics, 2003, Vol. 12, No. 3 227-232
© 2003 Oxford University Press

Role of oxidative stress in telomere shortening in cultured fibroblasts from normal individuals and patients with ataxia–telangiectasia

Andrei Tchirkov1,{dagger} and Peter M. Lansdorp1,2,*

1The Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada V5Z 1L3 and 2Department of Medicine, University of British Columbia, Vancouver, BC, Canada V5Z 4E3

Received August 21, 2002; Accepted November 26, 2002

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.

* To whom correspondence should be addressed at: Terry Fox Laboratory, BC Cancer Agency, 601 West 10th Avenue, Vancouver, BC, Canada V5Z 1L3. Tel: +1 6048776070, ext. 3026; Fax: +1 6048770712; E-mail: plansdor{at}bccancer.bc.ca

{dagger} Present address: Département de Radiothérapie, Centre Jean Perrin, Clermont-Ferrand 63011, France.


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