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The critical cellular defect(s) and basis for cell killing by ionizing radiation in ataxia-telangiectasia (A-T) are unknown. We use the topoisomerase I inhibitor camptothecin (CPT), which kills mainly S-phase cells and induces DSBs predominantly in replication forks, to show that A-T cells are defective in the repair of this particular subclass of DSBs. CPT-treated A-T cells reaching G2 have abnormally high levels of chromatid exchanges (viewed as prematurely condensed G2 chromosomes); aberrations in normal cells are mostly chromatid breaks. Transfectants of A-T cells with the wild-type ATM cDNA are corrected for CPT sensitivity, chromatid aberrations, and the DSB repair defect. These data suggest that in normal cells ATM, the A-T protein, probably recognizes DSBs in active replicons and targets the repair machinery to the breaks; in addition, the ATM protein is involved in the suppression of low-fidelity, adventitious rejoining between replication-associated DSBs. The loss of ATM functions therefore leads to genome destabilization, sensitivity to DSB-inducing agents and to the cancer-promoting illegitimate exchange events that follow.

Original publication




Journal article


Biochem Biophys Res Commun

Publication Date





317 - 325


Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Camptothecin, Cell Cycle, Cell Cycle Proteins, Cell Line, Cell Survival, DNA Damage, DNA Repair, DNA Replication, DNA-Binding Proteins, Enzyme Inhibitors, Humans, Protein-Serine-Threonine Kinases, Proteins, Recombinant Proteins, Recombination, Genetic, Sister Chromatid Exchange, Topoisomerase I Inhibitors, Transfection, Tumor Suppressor Proteins