Homologous recombination induced by replication inhibition, is stimulated by expression of mutant p53.
Cell cycle control, faithful DNA replication, repair and recombination are associated in a network of pathways controlling genome maintenance. In mammalian cells, inhibition of replication produces DNA breaks and induces RAD51-dependent recombination, in a late step. Here we examine whether the status of p53 affects this process in mouse L-cells containing a recombination substrate. We show that expression of the mutant (His175)p53 strongly stimulates recombination induced by aphidicolin, in a late step (kinetically related to the RAD51 step). Mutant p53 stimulates recombination induced by the replication elongation inhibitors (aphidicolin, hydroxyurea and Ara-C) but is without effect on recombination induced by the initiation inhibitors (mimosine and ciclopirox olamine). We compared the impact of several p53 mutations showing different effects on the G1 checkpoint and on recombination. We show that the mutant (Pro273)p53 protein, which does not alter the G1 checkpoint, strongly stimulates recombination induced by elongation inhibitors. These results show that p53 can act on recombination induced by replication arrest independently of its role in the G1 checkpoint. An action of p53 via the RAD51 pathway is discussed.
Saintigny
Yannick
Y
UMR217 CNRS-CEA, CEA, Direction des Sciences du Vivant, Département de Radiobiologie et Radiopathologie, 60-68 avenue du Général Leclerc, 92 265 Fontenay aux Roses, cedex, France.
Lopez
Bernard S
BS
D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D000077768:Ciclopirox; D003561:Cytarabine / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression; D016158:Genes, p53 / Q000235:genetics*; D006918:Hydroxyurea / Q000494:pharmacology; D051379:Mice; D008898:Mimosine / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology; D011995:Recombination, Genetic / Q000187:drug effects / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D011728:Pyridones; D016159:Tumor Suppressor Protein p53; D003561:Cytarabine; D000077768:Ciclopirox; D016590:Aphidicolin; D008898:Mimosine; D006918:Hydroxyurea