The role of O6-methylguanine in human cell killing, sister chromatid exchange induction and mutagenesis: a review.
O6-methylguanine (O6mG) produced in DNA by such SN1 methylating agents as N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) has been suggested by some to be the lesion that leads to certain biological endpoints in mammalian cells: cell killing, sister chromatid exchange (SCE) production, mutagenesis and cellular transformation. Other evidence is interpreted as inconsistent with this point of view. The finding of Karran & Williams (1985) that O6mG delivered to cells in culture resulted in the depletion of the activity of the protein responsible for repair of O6mG in DNA (O6mG-DNA methyltransferase, O6MT) provided a tool for the assessment of the role of O6mG in producing biological endpoints. In this paper we review much of the literature on human cells pertinent to this question. In addition we present our survival data obtained using the depletion technique of Karran & Williams as well as data supporting a model invoking a mismatch and excision response to O6mG proposed by Sklar & Strauss (1980). Although data linking O6mG to causation are inconclusive, it is premature to conclude that O6mG is not a lesion lethal to certain cultured cells.
Day
R S
RS
Department of Medicine, Cross Cancer Institute, Edmonton, Alberta, Canada.
Babich
M A
MA
Yarosh
D B
DB
Scudiero
D A
DA
D000256:Adenoviridae / Q000187:drug effects; D001482:Base Composition; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004279:DNA, Viral; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009154:Mutation; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D004279:DNA, Viral; D008769:Methylnitronitrosoguanidine; D006147:Guanine; C008449:O-(6)-methylguanine