On the quantitative relationship between O6-methylguanine residues in genomic DNA and production of sister-chromatid exchanges, mutations and lethal events in a Mer- human tumor cell line.
O6-Methylguanine (m6G) is an altered base produced in DNA by SN1 methylating agents such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). This lesion is repaired by the protein O6-methylguanine-DNA methyltransferase (MGMT) in normal human cell lines, but is not repaired in certain human tumor lines that are termed Mex- or Mer-. Compared with repair-proficient cell lines, such repair-deficient tumor lines are hypersensitive to the production by MNNG of sister-chromatid exchanges (SCE), mutations and lethality. We report here that MNNG treatment produces 1 SCE for every 42 +/- 10 m6G formed in the genome of Mer- tumor cells, 1 6TG-resistant mutant for every 8 (range of 5-14) m6G produced statistically in the coding region of the hypoxanthine phosphoribosyltransferase gene, and 1 lethal event per 6650 +/- 1200 m6G. In addition, in vitro base mismatch incision at m6G: BrU pairs was similar to that at m6G: T pairs, the lesions that likely initiate SCE production. We conclude that m6G residues in genomic DNA are very recombinogenic as well as highly mutagenic in Mer- human tumor cells. The results are interpreted in terms of the relationship between methylation-induced SCE and G: T mismatch recognition.
Rasouli-Nia
A
A
Department of Medicine, Cross Cancer Institute, Edmonton, Canada.
Sibghat-Ullah
Mirzayans
R
R
Paterson
M C
MC
Day
R S
RS
D001483:Base Sequence; D016923:Cell Death; D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D004260:DNA Repair; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D008780:Methyltransferases / Q000378:metabolism; D008969:Molecular Sequence Data; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D009692:Nucleic Acid Heteroduplexes; D019853:O(6)-Methylguanine-DNA Methyltransferase; D012854:Sister Chromatid Exchange; D013866:Thioguanine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D009153:Mutagens; D009692:Nucleic Acid Heteroduplexes; D008769:Methylnitronitrosoguanidine; D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013866:Thioguanine