Extra-chromosomal telomeric DNA in cells from Atm(-/-) mice and patients with ataxia-telangiectasia

Ataxia-telangiectasia (AT) is an autosomally recessive human genetic diseas e with pleiotropic defects such as neurological degeneration, immunodeficie ncy, chromosomal instability, cancer susceptibility and premature aging. Ce lls derived from AT patients and ataxia-telangiectasia mutated (ATM)-defici ent mice show slow growth in culture and premature senescence. ATM, which b elongs to the P13 kinase family along with DNA-PK, plays a major role in si gnaling the p53 response to DNA strand breaks. Telomere maintenance is pert urbed in yeast strains lacking genes homologous to ATM and cells from patie nts with AT have short telomeres. We examined the length of individual telo meres in cells from Atm(-/-) mice by fluorescence in situ hybridization. Te lomeres were extensively shortened in multiple tissues of Atm(-/-) mice. Mo re than the expected number of telomere signals was observed in interphase nuclei of Atm(-/-) mouse fibroblasts. Signals corresponding to 5-25 kb of t elomeric DNA that were not associated with chromosomes were also noticed in Atm(-/-) metaphase spreads. Extrachromosomal telomeric DNA was also detect ed in fibroblasts from AT patients and may represent fragmented telomeres o r by-products of defective replication of telomeric DNA. These results sugg est a role of ATM in telomere maintenance and replication, which may contri bute to the poor growth of Atm(-/-) cells and increased tumor incidence in both AT patients and Atm(-/-) mice.