Accelerated telomere shortening and telomere abnormalities in radiosensitive cell lines.
We examined telomere maintenance in cells of 11 primary fibroblast cell lines with differing genetic defects that confer sensitivity to ionizing radiation. These included cell lines derived from patients with ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, defective Artemis, DNA ligase I and DNA ligase IV, an immunodeficient patient with a defect in DNA double-strand break repair, and a patient diagnosed with xeroderma pigmentosum who, in addition, showed severe clinical sensitivity to ionizing radiation. Our results, based on Southern blot, flow-FISH and Q-FISH (quantitative FISH) measurements, revealed an accelerated rate of telomere shortening in most cell lines derived from the above patients compared to cell lines from normal individuals or a cell line isolated from a heterozygotic parent of one radiosensitive patient. This accelerated telomere shortening was accompanied by the formation of chromatin bridges in anaphase cells, indicative of the early loss of telomere capping function and in some cases low levels of chromosome abnormalities in metaphase cells. We also analyzed telomere maintenance in mouse embryonic stem cells deficient in Brca1, another defect that confers radiosensitivity. Similarly, these cells showed accelerated telomere shortening and mild telomere dysfunction in comparison to control cells. Our results suggest that mechanisms that confer sensitivity to ionizing radiation may be linked with mechanisms that cause telomere dysfunction.
Cabuy
E
E
Brunel Institute of Cancer Genetics and Pharmacogenomics, School of Health Sciences and Social Care, Brunel University, Uxbridge, Middlesex, UB8 3PH, United Kingdom.
Newton
C
C
Joksic
G
G
Woodbine
L
L
Koller
B
B
Jeggo
P A
PA
Slijepcevic
P
P
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics* / Q000528:radiation effects*; D002869:Chromosome Aberrations; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D051379:Mice; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000235:genetics*; D013234:Stem Cells / Q000502:physiology / Q000648:ultrastructure; D016615:Telomere / Q000235:genetics* / Q000648:ultrastructure