Human Molecular Genetics, 2001, Vol. 10, No. 5 519-528
© 2001 Oxford University Press
Extra-chromosomal telomeric DNA in cells from Atm–/– mice and patients with ataxia-telangiectasia
1Terry Fox Laboratory, British Columbia Cancer Agency, 601 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada, 2Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA, 3School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0627, USA and 4Department of Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada
Ataxia-telangiectasia (AT) is an autosomally recessive human genetic disease with pleiotropic defects such as neurological degeneration, immunodeficiency, chromosomal instability, cancer susceptibility and premature aging. Cells derived from AT patients and ataxia-telangiectasia mutated (ATM)-deficient mice show slow growth in culture and premature senescence. ATM, which belongs to the PI3 kinase family along with DNA-PK, plays a major role in signaling the p53 response to DNA strand breaks. Telomere maintenance is perturbed in yeast strains lacking genes homologous to ATM and cells from patients with AT have short telomeres. We examined the length of individual telomeres in cells from Atm–/– mice by fluorescence in situ hybridization. Telomeres were extensively shortened in multiple tissues of Atm–/– mice. More than the expected number of telomere signals was observed in interphase nuclei of Atm–/– mouse fibroblasts. Signals corresponding to 5–25 kb of telomeric DNA that were not associated with chromosomes were also noticed in Atm–/– metaphase spreads. Extrachromosomal telomeric DNA was also detected in fibroblasts from AT patients and may represent fragmented telomeres or by-products of defective replication of telomeric DNA. These results suggest a role of ATM in telomere maintenance and replication, which may contribute to the poor growth of Atm–/– cells and increased tumor incidence in both AT patients and Atm–/– mice.
+ Present address: Center for Radiological Research, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA
§ To whom correspondence should be addressed at: Terry Fox Laboratory, British Columbia Cancer Agency, 601 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada. Tel: +1 604 877 6070; Fax: +1 604 877 0712; Email: plansdor@bccancer.bc.ca
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