Mutant p53 proteins stimulate spontaneous and radiation-induced intrachromosomal homologous recombination independently of the alteration of the transactivation activity and of the G1 checkpoint

We report here a systematic analysis of the effects of different p53 mutati ons on both spontaneous and radiation-stimulated homologous recombination i n mouse L cells. In order to monitor different recombination pathways, we u sed both direct and inverted repeat recombination substrates. In each line bearing one of these substrates, we expressed p53 proteins mutated at posit ions: 175, 248 or 273, p53 mutations leading to an increased spontaneous re combination rate also stimulate radiation-induced recombination. The effect on recombination may be partially related to the conformation of the p53 p rotein. Moreover, p53 mutations act on recombination between direct repeats as well as between inverted repeats indicating that strand invasion mechan isms are stimulated. Although all of the p53 mutations affect the p53 trans activation activity measured on the WAF1 and MDM2 gene promoters, no correl ation between the transactivation activity and the extent of homologous rec ombination can be drawn. Finally, some p53 mutations do not affect the G1 a rrest after radiation but stimulate radiation-induced recombination. These results show that the role of p53 on transactivation and G1 cell cycle chec kpoint is separable from its involvement in homologous recombination. A dir ect participation of p53 in the recombination mechanism itself is discussed .