Wild-type p53 inhibits replication-associated homologous recombination.
In mammalian cells homologous recombination is stimulated, when the replication fork stalls at DNA breaks or unrepaired lesions. The tumor suppressor p53 downregulates homologous recombination independently of its transcriptional transactivation function and has been linked to enzymes of DNA recombination and replication. To study recombination with respect to replication, we utilized a SV40 virus based assay, to follow the synchronous events after primate cell infection. gamma-ray treatment at different times after viral entry unveiled an increase of interchromosomal exchange frequencies, when the damage was introduced during DNA synthesis. Elevated recombination frequencies were fully suppressed by p53. With respect to the downregulation of spontaneous recombination, we noticed a requirement for active p53 molecules, when replication started. After a transient treatment with replication inhibitors, we observed inhibition of the drug induced recombination by p53, particularly for the elongation inhibitor aphidicolin. Consequently, we propose that p53 is a surveillance factor of homologous recombination at replication forks, when they stall as a consequence of endogenous or of exogenously introduced damage.
Universitätsfrauenklinik und Poliklinik, Prittwitzstrasse 43, D-89075 Ulm, Germany.
Christine
C
Janz
Lisa
L
Wiesmüller
D000818:Animals; D016590:Aphidicolin / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D002875:Chromosomes / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics*; D005720:Gamma Rays; D000882:Haplorhini; D011995:Recombination, Genetic; D013539:Simian virus 40 / Q000235:genetics / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D016590:Aphidicolin