Involvement of p53 in X-ray induced intrachromosomal recombination in mice

The tumor suppressor gene Trp53 (also known as p53) is the most frequently mutated gene in human cancers. p53 is induced in response to DNA damage and effects a G(1) cell cycle arrest. It is believed that p53 plays a key role in maintaining genomic integrity following exposure to DNA-damaging agents . We determined the frequency of spontaneous and DNA damage-induced homolog ous intrachromosomal recombination in p53-deficient mouse embryos. Homologo us intrachromosomal recombination events resulting in deletions at the pink eyed unstable (p(un)) locus result in reversion to the p gene, Reversions occurring in embryonic premelanocytes give rise to black spots on the gray fur of the offspring. Pregnant C57BL/6J p(un)/p(un) p53(+/-) mice were expo sed to X-rays (1 Gy) or administered benzo[a]pyrene (B[a]P; 30 osignificant ly different compared withr 150 mg/kg i.p.) 10 days after conception. Frequ encies of sponsed the recombination frequency in wild-type and p53(+/-)tane ous p(un) reversions in p53(-/-) and p53(+/-) animals were not their wild-t ype littermates. X-ray treatment increa, but surprisingly not in p53(-/-) o ffspring. In contrast, B[a]P treatment caused a dose-dependent increase in p(un) reversion frequencies in all three genotypes. Western blot analysis o f embryos indicated that p53 protein levels increased similar to 3-fold fol lowing X-ray treatment, while B[a]P had no effect on p53 expression, These results are in agreement with the proposal that p53 is involved in the DNA damage response following X-ray exposure and suggest that X-ray-induced dou ble-strand breaks are processed differently in p53(-/-) animals.