Dose-rate effect in radiation mutagenesis: role of p53 gene

Normal function of the p53 gene is integral to the cellular response to genotoxic stress. One prediction arising from this that p53 deficiency results in an increased survival of cells bearing DNA damage, thereby leading to an increased mutation frequency and eventually predisposing to malignancy, either by failure to permit repair of damaged DNA or by failed deletion of mutation bearing cells. In order to investigate the in vivo role of p53 in surveillance against mutation, and particularly to address the significance of p53-dependent apoptosis, we have used p53 null and wild-type p53(+/+) mice to determine the mutation frequency at the TCR locus following exposure to gamma-irradiation. After gamma-irradiation with 3 Gy, the mutation frequency of mice T-lymphocytes defective in T-cell receptor (TCR) gene expression was higher than the control level at acute exposure (1020 mGy/min). However, when an equal dose of 3 Gy was given but at a lower dose-rate (1.2 mGy/min), the frequency of mutant T-lymphocytes did not increase at all for p53(+/+) mice which are capable of p53-dependent apoptosis, whereas the dose of 3 Gy remained mutagenic for p53(-/-) mice, which are unable to carry out p53-dependent apoptosis. The frequency of mutant T-lymphocytes increased rapidly to a maximum of 4x10 -3 at 8-10 days after acute gamma-irradiation, then gradually decreased with half-life of 13 days for p53(+/+) mice. Whereas in the p53(-/-) mice, the peak TCR mutation frequency remained constant for up to 28 days and did not decrease at all in the course of the experiment. These results indicate that p53 deficiency should lead to an increased mutation frequency by failed elimination of the mutagenic damage from the irradiated tissues. Hence, complete repair of genotoxic damage requires the two mechanisms, p53-dependent apoptotic tissue repair as well as the well-known DNA repair