Radiation-induced genomic instability triggered by telomere dysfunction

Radiation induces genomic instability in the progeny of irradiated cells. However, there is only poor scientific evidence to clarify the nature of an initial event that leads to genome rearrangement triggered by radiation. To know the mechanism of genomic instability by radiation, we investigated the stability of an irradiated chromosome in the unirradiated environment by a chromosome transfer method. Mouse A9 cells containing a human chromosome 4 or 11 were irradiated with X-rays, and then the irradiated human chromosome was transferred into unirradiated mouse m5S cells using a microcell-mediated chromosome transfer. Chromosome aberrations were analyzed by whole chromosome painting using a probe specific for human chromosome 4 or 11. The chromosome analysis revealed that the irradiated chromosome per se showed the unstable nature in the unirradiated recipient cells. The chromosome instability was characterized by end-to-end telomeric fusions possibly mediated by radiation-induced telomere dysfunction. A similar result was obtained in radiosensitive scid mouse cells and Atm knock out mouse cells that were derived from secondary surviving colonies after X-irradiation. We demonstrated that both scid mouse cells and Atm-deficient mouse cells were susceptible to delayed induction of end-to-end fusions mediated by telomeric instability over 20 cell divisions post-irradiation. In Atm-deficient mouse cells, the telomeric instability was characterized by the abnormal telomere FISH signals including loss of the signals and the extra-chromosomal signals that were associated and/or not associated with chromosome ends. These results suggest that both DNA-PKcs and Atm protein play an essential role for telomere maintenance and also that radiation promotes telomere dysfunction. On the basis of the present results, we propose that radiation-induced delayed chromosomal instability is triggered by telomere dysfunction and that telomere is a critical target for induction of genomic instability by radiation