Increased frequency of DNA deletions in pink-eyed unstable mice carrying a mutation in the Werner syndrome gene homologue.
Werner syndrome (WS) is a rare autosomal recessive disorder characterized by genomic instability and the premature onset of a number of age-related diseases, including cancers. Accumulating evidence indicates that the WS gene product is involved in resolving aberrant DNA structures that may arise during the process of DNA replication and/or transcription. To estimate the frequency of DNA deletions directly in the skin of mouse embryos, mice with a deletion of part of the murine WRN helicase domain were created. These mutant mice were then crossed to the pink-eyed unstable animals, which have a 70 kb internal duplication at the pink-eyed dilution (p) gene. This report indicates that the frequency of deletion of the duplicated sequence at the p locus is elevated in mice with a mutation in the WRN allele when compared with wild-type mice. In addition, the inhibitor of topoisomerase I camptothecin also increases the frequency of deletion at the p locus. This frequency is even more elevated in WRN mutant mice treated with camptothecin. In contrast, while the inhibition of poly(ADP-ribose) polymerase (PARP) activity by 3-aminobenzamide increases the frequency of DNA deletion, mutant WRN mice are not significantly more sensitive to the inhibition of PARP activity than wild-type animals.
Lebel
Michel
M
Centre de Recherche en Cancérologie de l'Université Laval, Pavillon Hôtel-Dieu de Québec, CHUQ, 9 McMahon Street, Québec City, Québec G1R 2J6, Canada. michel.lebel@crhdq.ulaval.ca
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D002352:Carrier Proteins; D004265:DNA Helicases / Q000235:genetics*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005090:Exodeoxyribonucleases; D005127:Eye Color / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics*; D020131:Genes, Duplicate / Q000235:genetics; D005838:Genotype; D006200:Hair Color / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D016296:Mutagenesis / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D053484:RecQ Helicases; D017384:Sequence Deletion / Q000235:genetics*; D017385:Sequence Homology; D059004:Topoisomerase I Inhibitors; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase
D001549:Benzamides; D002352:Carrier Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C489600:OCA2 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059004:Topoisomerase I Inhibitors; C076239:P protein, mouse; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin