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 homologous intrachromosomal recombination in p53-deficient mouse embryos. Homologous 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 exposed to X-rays (1 Gy) or administered benzo¿apyrene (B¿aP; 30 or 150 mg/kg i.p.) 10 days after conception. Frequencies of spontaneous p(un) reversions in p53(-/-) and p53(+/-) animals were not significantly different compared with their wild-type littermates. X-ray treatment increased the recombination frequency in wild-type and p53(+/-), but surprisingly not in p53(-/-) offspring. In contrast, B¿aP treatment caused a dose-dependent increase in p(un) reversion frequencies in all three genotypes. Western blot analysis of embryos indicated that p53 protein levels increased approximately 3-fold following X-ray treatment, while B¿aP 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 double-strand breaks are processed differently in p53(-/-) animals.
Aubrecht
J
J
Department of Cancer Cell Biology, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 2115, USA.
Secretan
M B
MB
Bishop
A J
AJ
Schiestl
R H
RH
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D017353:Gene Deletion; D016158:Genes, p53; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*
D002273:Carcinogens; D001564:Benzo(a)pyrene