Abstract
The major risks of radiation exposure have been shown experimentally with mice to approach zero risk with decreasing low dose-rate irradiation. This demonstrates the critical contribution of DNA repair. However, DNA repair is not perfect. There must be defense mechanisms other than DNA repair. In order to investigate the in vivo role of p53 in surveillance against mutation, and particularly to address the effect of dose rate and the significance of p53-dependent apoptosis, we have used wild-type p53(+/+) and null p53(-/-) mice to determine the mutant frequency at the TCR locus following exposure to gamma-rays. After acute gamma-irradiation with 3 Gy (@ 61 Gy/h), the TCR mutation frequency was higher than the control level. However, when an equal dose of 3 Gy was given but at a lower dose-rate of 0.07 Gy/h, the frequency of TCR mutants did not increase at all for p53(+/+) mice, whereas the same dose of 3 Gy remained mutagenic for p53(-/-) mice, which are unable to carry out p53-dependent apoptosis. This can explain why there is no detectable increase in mutations in p53(+/+) mice after protected irradiation with 3 Gy because, if a fraction of apoptosis-sensitive cells retain unrepaired DNA damage after gamma-irradiation, almost all of them deleted by p53-dependent apoptosis. These results indicate that the p53 gene is indispensable for a threshold effect in the risk of radiation at low doses or dose-rates.
