HYPERSENSITIVITY OF ATAXIA-TELANGIECTASIA FIBROBLASTS TO IONIZING-RADIATION IS ASSOCIATED WITH A REPAIR DEFICIENCY OF DNA DOUBLE-STRAND BREAKS

We have studied the intrinsic radiosensitivity, repair of potentially lethal damage (PLD) and the repair rate of radiation-induced DNA doubl e-strand breaks (DSB) in 11 non-transformed human fibroblast cell line s, four of which were homozygous for the A-T mutation and two that wer e heterozygous (A-TH). All the experiments were done on cells in plate au phase of growth (97-99% of cells in G0/G1). With a dose of 30 Gy de livered at 4 degrees C, the A-T cell lines had faster repair rates of up to 6 h, after which the repair curve crossed that of the control so that the residual damage at 24 h was higher in the A-T cells. Irradia tion at 37 degrees C at low dose rate (1 cGy.min(-1)) produced even mo re marked differences between the A-T cells and controls: the residual DSB level was always higher in A-T cells than controls at doses of 5- 40 Gy, due to defective repair of a small fraction of DSB in A-T cells . The two protocols showed DSB repair rates for the A-TH cell lines th at were intermediate between those of the A-T and control cells. There was a quantitative relationship between the residual DSB after irradi ation at 37 degrees C and the intrinsic radiosensitivity, and with the extent of PLD repair. There were very few apoptotic cells in the non- transformed control and A-T cell lines, both before and after irradiat ion. In combination, these results support the contention that the def ective repair of DSB is a mechanism of the hypersensitivity linked to the A-T mutation.