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

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)-defici...

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Bibliographic Details
Published in:Human molecular genetics 2001-03, Vol.10 (5), p.519-528
Main Authors: PRAKASH HANDE, M, BALAJEE, Adayabalam S, TCHIRKOV, Andrei, WYNSHAW-BORIS, Anthony, LANSDORP, Peter M
Format: Article
Language:English
Subjects:
Animals
Ataxia Telangiectasia - genetics
Ataxia Telangiectasia Mutated Proteins
Biological and medical sciences
Blotting, Southern
Cell Cycle Proteins
Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...)
DNA - genetics
DNA-Binding Proteins
Humans
In Situ Hybridization, Fluorescence
Medical genetics
Medical sciences
Mice
Mice, Knockout
Nucleic Acid Hybridization
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - physiology
Telomere
Tumor Suppressor Proteins
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Summary: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.
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/10.5.519