Influence of DNA repair on mutation spectra in Salmonella.
This paper reviews the influence of DNA repair on spontaneous and mutagen-induced mutation spectra at the base-substitution (hisG46) and -1 frameshift (hisD3052) alleles present in strains of the Salmonella (Ames) mutagenicity assay. At the frameshift allele (mostly a CGCGCGCG target), DeltauvrB influences the frequency of spontaneous hotspot mutations (-CG), duplications, and deletions, and it also shifts the sites of deletions and duplications. Cells with pKM101+DeltauvrB spontaneously produce complex frameshifts (frameshifts with an adjacent base substitution). The spontaneous frequency of 1-base insertions or concerted (templated) mutations is unaffected by DNA repair, and neither mutation is inducible by mutagens. Glu-P-1, 1-nitropyrene (1NP), and 2-acetylaminofluorene (2AAF) induce only hotspot mutations and are unaffected by pKM101, whereas benzo(a)pyrene and 4-aminobiphenyl induce only hotspot in pKM101(-), and hotspot plus complex in pKM101(+). At the base-substitution allele (mostly a CC/GG target), the DeltauvrB allele increases spontaneous transitions in the absence of pKM101 and increases transversions in its presence. The frequency of suppressor mutations is decreased 4x by DeltauvrB, but increased 7. 5x by pKM101. Both repair factors cause a shift in the proportion of mutations to the second position of the CC/GG target. With UV light and gamma-rays, the DeltauvrB allele increases the proportion of transitions relative to transversions. pKM101 is required for mutagenesis by Glu-P-1 and 4-AB, and the types and positions of the substitutions are not altered by the addition of the DeltauvrB allele. Changes in DNA repair appear to cause more changes in spontaneous than in mutagen-induced mutation spectra at both alleles. There is a high correlation (r(2)=0.8) between a mutagen's ability to induce complex frameshifts and its relative base-substitution/frameshift mutagenic potency. A mutagen induces the same primary class of base substitution in TA100 (DeltauvrB, pKM101) as it does in Escherichia coli, mammalian cells, or rodents as well as in the p53 gene of human tumors associated with exposure to that mutagen. Thus, a mutagen induces the same primary class of base substitution in most organisms, reflecting the conserved nature of DNA replication and repair processes.
DeMarini
D M
DM
Environmental Carcinogenesis Division, US Environmental Protection Agency, MD-68, 86 Alexander Drive, Research Triangle Park, NC 27711, USA. demarini.david@epa.gov
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D004260:DNA Repair / Q000235:genetics*; D004269:DNA, Bacterial / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D016368:Frameshift Mutation; D006801:Humans; D008969:Molecular Sequence Data; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D017354:Point Mutation; D012475:Salmonella / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion
D004269:DNA, Bacterial; D009153:Mutagens