Radiosensitivity in Ataxia-telangiectasia: Anomalies in Radiation-induced Cell Cycle Delay

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Abstract
A number of anomalies have been described in the progression of ataxia-telangiectasia (AT) cells through the cell cycle post-irradiation. Some uncertainty still exists as to whether AT cells show increased or reduced division delay after exposure to ionizing radiation. We have attempted to resolve the apparent inconsistencies that exist by investigating the effects of radiation on AT cells at various stages of the cell cycle. Specific labelling of S phase cells with 5-bromodeoxyuridine (BrdU) followed by irradiation caused a prolonged accumulation of these cells in G2/M phase with only 2-7% of AT cells progressing through to G1 24h post-irradiation. In contrast, 23-28% of control cells irradiated in S phase reached G1 by 24 h after irradiation. As observed previously with AT fibroblasts, AT lymphoblastoid cells irradiated in G1 phase did not experience a delay in entering S phase. After progressing through S phase these cells also were delayed in G2/M, but not to the same extent as irradiated S phase cells. On the other hand, when AT cells were irradiated in G2 phase they showed less delay initially in entry to mitosis and the subsequent G1 phase than did irradiated control cells. The overall results demonstrate that AT cells fail to show an initial delay in transitions between the G1/S and G2/M phases of the cell cycle and in progression through these phases post-irradiation, but in the long-term, after passage through S phase, they experience a prolonged delay in G2/M. Since several AT complementation groups are represented in this study, the cell cycle anomalies appear to be universal in AT. These results implicate deficiencies in control of cell cycle progression in the increased radiosensitivity and cancer predisposition in AT.