Influence of nucleotide excision repair on N-hydroxy-2-acetylaminofluorene-induced mutagenesis studied in λlacZ-transgenic mice
article
To study the influence of nucleotide excision repair (NER) on mutagenesis in vivo, ERCC1+/-, XPA-/-, and wild-type (ERCC1+/+ and XPA+/+, respectively) λlacZ-transgenic mice were treated i.p. with N-hydroxy-2-acetylaminofluorene (N-OH-AAF) and lacZ mutant frequencies were determined in liver. No significant effect of the treatment on the mutant Frequency in wild-type or ERCC1-heterozygous mice was observed. The liver mutant frequency appeared to be significantly increased in treated XPA-/- mice only. To distinguish N-OH-AAF-induced from spontaneous mutations, lacZ mutants derived from treated XPA-/- mice were subjected to DNA-sequence analysis and the spectrum obtained was compared to that established for lacZ mutants in liver of PBS-treated λlacZ-transgenic mice of the parent strain 40.6. The N-OH-AAF-induced mutation spectrum appeared to be significantly different from the spontaneous mutation spectrum: the former consisted of mainly (19/22) single bp substitutions targeted at G, of which the majority (12/19) were G:C → T:A transversions, suggesting that N-(deoxyguanosin-8-yl)-2-aminofluorene [dG-C8-AF], the major DNA adduct in N-OH-AAF-treated mice, is the premutagenic lesion. After analysis of 21 spontaneous mutants, only ten single bp substitutions targeted at G were found, of which five were G:C → T:A transversions. This study with XPA-/- λlacZ-transgenic mice shows that one of the components of NER, that is, the XPA protein, suppresses mutagenesis in vivo.
Topics
LacZMutagenesisN-hydroxy-2-acetylaminofluoreneNucleotide excision repairTransgenic miceFluorenylacetohydroxamic acidNucleotideAnimal experimentControlled studyDna sequenceExcision repairFemaleMaleMouseMutagenesisMutagenicityMutation rateNonhumanSpontaneous mutationTransgenic mouseAnimalsDNA RepairDNA-Binding ProteinsEndonucleasesHydroxyacetylaminofluoreneLac OperonMaleMiceMice, TransgenicMutagensProteins
TNO Identifier
234395
ISSN
08936692
Source
Environmental and Molecular Mutagenesis, 31(1), pp. 41-47.
Pages
41-47
Files
To receive the publication files, please send an e-mail request to TNO Repository.