Development of a general model of chromosome aberration formation

The formation of chromosome aberrations which result from DNA damage is mediated by the probability of coincidentally repairing regions. Therefore, factors which alter the rate of repair of DNA damage result in a greater likelihood of forming chromosome aberrations. Coincidentally repairing regions are hypothesized to be important in the formation of chromosome aberrations because they are more likely to form DNA strand exchange events. Pyrimidine nucleosides (e.g. CldU) induce intra-chromosomal exchanges of DNA replication products. The presence of CldU in DNA is predicted, therefore, to increase the likelihood of forming chromosome aberrations since its presence tends to initiate exchange events. CHO-K1BH4 cells, substituted with BrdU or CldU, were treated with a variety of clastogens in an attempt to test the hypothesis described above. CldU was found to enhance the level of chromosome aberrations (specifically exchange-type chromosome aberrations) induced by X rays, bleomycin, neutrons and restriction endonucleases. The enhancement of chromosome aberrations by CldU was greatest for X rays. This reflects a much higher probability of CldU-induced misrepair of X ray-induced base damage, since such damage is almost certainly not induced by RE and only to a small extent by neutrons. The mechanism of chromosome aberration formation proposed for CHO cells was used for determining the nature of the defect in repair found in cells from individuals suffering from ataxia telangiectasia (AT). AT cells are sensitive to X rays and RE. The presence of CldU in the DNA of X-irradiated normal lymphoblastoid cells resulted in an enhancement of the level of X ray-induced chromosome aberrations, but no effect on the level of X ray-induced chromosome aberrations in AT cells. The results are consistent with a defect in the rate repair of DNA damage in AT cells. We conclude that chromosome aberrations are the result of misrepair of DNA damage that results in the formation of an exchange event. Thus, the frequency of induced chromosome aberrations can be increased by increasing the likelihood of an exchange event. The model test system developed in this work is useful in studying human repair defective cell lines.