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
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
Present address: Département de Radiothérapie, Centre Jean Perrin, Clermont-Ferrand 63011, France.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. A. Lemon, C. D. Rollo, and D. R. Boreham Elevated DNA damage in a mouse model of oxidative stress: impacts of ionizing radiation and a protective dietary supplement Mutagenesis, November 1, 2008; 23(6): 473 - 482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Spyridopoulos, Y. Erben, T. H. Brummendorf, J. Haendeler, K. Dietz, F. Seeger, C. K. Kissel, H. Martin, J. Hoffmann, B. Assmus, et al. Telomere Gap Between Granulocytes and Lymphocytes Is a Determinant for Hematopoetic Progenitor Cell Impairment in Patients With Previous Myocardial Infarction Arterioscler. Thromb. Vasc. Biol., May 1, 2008; 28(5): 968 - 974. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Yanowitz Genome Integrity Is Regulated by the Caenorhabditis elegans Rad51D Homolog rfs-1 Genetics, May 1, 2008; 179(1): 249 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. F. Cherkas, J. L. Hunkin, B. S. Kato, J. B. Richards, J. P. Gardner, G. L. Surdulescu, M. Kimura, X. Lu, T. D. Spector, and A. Aviv The Association Between Physical Activity in Leisure Time and Leukocyte Telomere Length Arch Intern Med, January 28, 2008; 168(2): 154 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Muftuoglu, H. K. Wong, S. Z. Imam, D. M. Wilson III, V. A. Bohr, and P. L. Opresko Telomere Repeat Binding Factor 2 Interacts with Base Excision Repair Proteins and Stimulates DNA Synthesis by DNA Polymerase {beta} Cancer Res., January 1, 2006; 66(1): 113 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. Opresko, J. Fan, S. Danzy, D. M. Wilson III, and V. A. Bohr Oxidative damage in telomeric DNA disrupts recognition by TRF1 and TRF2 Nucleic Acids Res., February 24, 2005; 33(4): 1230 - 1239. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Spyridopoulos, J. Haendeler, C. Urbich, T. H. Brummendorf, H. Oh, M. D. Schneider, A. M. Zeiher, and S. Dimmeler Statins Enhance Migratory Capacity by Upregulation of the Telomere Repeat-Binding Factor TRF2 in Endothelial Progenitor Cells Circulation, November 9, 2004; 110(19): 3136 - 3142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Kurz, S. Decary, Y. Hong, E. Trivier, A. Akhmedov, and J. D. Erusalimsky Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells J. Cell Sci., May 1, 2004; 117(11): 2417 - 2426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Bai and J. P. Murnane Telomere Instability in a Human Tumor Cell Line Expressing NBS1 With Mutations at Sites Phosphorylated by ATM Mol. Cancer Res., December 1, 2003; 1(14): 1058 - 1069. [Abstract] [Full Text] [PDF]
|
|