Apoptotic repair of genotoxic tissue damage and the role of p53 gene.
The spontaneous mutation rate per replication per genome is nearly invariant in microbes; however, the rate of spontaneous genomic mutations in higher eukaryotes is much higher. Furthermore, the mutation rates per locus per generation among Drosophila, mice and humans are similar, despite the large differences in generation time. A simple explanation for these findings is that mice and humans have a specific antimutagenic mechanism that is lacking in Drosophila. I propose that apoptotic repair-deletion of genotoxic damage-bearing cells-operates in mammalian germ cells and that it works more accurately in humans than in mice because of a slower rate of cell turnover and a longer generation time. It has been a long-standing puzzle that germline mutation frequencies decrease markedly as the dose-rate of radiation is lowered in mice but not in Drosophila. This can be readily explained by p53-dependent apoptotic repair, because the p53 gene is absent from the genome of Drosophila. Fetuses of p53+/+ mice have proficient apoptotic repair capacity for X-ray-induced teratogenic damage, but p53-null fetuses completely lack this capacity. Further, I propose that the primary role of the p53 gene is to guard germ cells and embryos from genotoxic damage. This implies that the tumour suppressor function of the p53 gene results from p53-dependent apoptotic deletion of cells with genotoxic damage. The reasoning behind this proposal is given by reviewing reports that Drosophila larvae are insensitive to tumour formation after irradiation. Finally, I discuss the genetic effects of radiation in humans.
Atomic Energy Research Institute, Kinki University, Higashiosaka 577, Japan. skondo@taurus.bekkoame.or.jp
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D000818:Animals; D016587:Antimutagenic Agents; D017209:Apoptosis / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans; D051379:Mice
D016587:Antimutagenic Agents