The role of p53 in protection of radiation mutagenesis

低剂量辐射的主要风险是诱变、致畸和致癌。所有这三种方法(实验)都表明，随着剂量率的降低，风险接近于零，这表明了DNA修复在低剂量率照射下的关键贡献。然而，DNA修复并不完美。除了DNA修复，还必须有防御机制。本文研究了P53对辐射诱导的T细胞受体(TCR)变异组分升高的影响，结果表明：(1)3Gy61Gyh急性伽玛射线照射后，T细胞受体(TCR)变异组分高于对照组。当照射剂量为3Gy时，低剂量率为0.07Gyh时，P53(+/+)小鼠的TCR变异体比例没有增加，而相同剂量的3GyTCR变异体比例对P53(-/-)小鼠仍有致突变作用，不能进行P53依赖的细胞凋亡。在P53(+/+)和P53(+/-)小鼠中，TCR变异部分分别在16周龄和20周龄时降至正常本底水平。在长时间的平坦期后，经照射的P53(+/+)小鼠的TCR变异体的比例在72周龄后显著增加，而在经照射的P53(+/-)小鼠的TCR变异体的比例在44周龄后显著增加。辐射后TCR变异体的延迟增加是由于p53依赖的细胞凋亡减少。这些结果表明，在低剂量或剂量率下，P53基因对于辐射风险的阈值效应是不可或缺的。

The major risks of low-dose radiation are mutagenesis, teratogenesis and carcinogenesis. All three have been shown (experimentally) to approach zero risk with decreasing dose rate, demonstrating the critical contribution of DNA repair at low dose-rate irradiation. However, DNA repair is not perfect. There must be defense mechanisms other than DNA repair. The influence of p53 on the radiation-induce elevation of T-cell receptor (TCR) variant fractions was examined in splenic T lymphocytes of p53-proficient and -deficient mice.(1)After acute gamma-irradiation with 3 Gy (@ 61 Gy/h), the TCR variant fraction 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 fraction of TCR variants 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.(2)Initially, the TCR variant fraction increased rapidly and reached its maximum level at 9 days after irradiation before decreasing gradually. In p53(+/+) and p53(+/-) mice, the TCR variant fraction fell to normal background levels at 16 and 20 weeks of age, respectively. After the long flat period, a significant re-increase in the fraction of TCR variants was found after 72 weeks of age in the irradiated p53(+/+) mice and after 44 weeks of age in the irradiated p53(+/-) mice. This delayed increase in TCR variants after irradiation is due to a reduction in 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-rate.