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N-methyl-N'-nitro-N-nitrosoguanidine-resistant HeLa S3 cells still have little O6-methylguanine-DNA methyltransferase activity and are hypermutable by alkylating agents. 1987

R Ishida, and T Takahashi

To clarify the involvement of O6-methylguanine (O6-MeG) in mutagenesis, we isolated N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-resistant cells, MR10-1 from HeLa S3 mer- cells. MR10-1 cells were 40 times more resistant to MNNG than the parental cells. MR10-1 cells were also significantly more resistant to N-methyl-N-nitrosourea and slightly more resistant to methyl methanesulfonate and dimethyl sulfate than parental cells. However, we found that MR10-1 cells had still little O6-MeG-DNA methyltransferase activity and were sensitive to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl- 3-(2-chloroethyl)-3-nitrosourea hydrochloride, like HeLa mer- cells, thereby showing that MR10-1 cells are still mer-. When induced 6-thioguanine (6TG)-resistant colonies were plotted as a function of the corresponding percentage survival, the resistant colonies of MR10-1 cells were induced much more frequently than in the case of HeLa mer- cells. However, induction of 6TG-resistant cells in both cell lines did not differ significantly in terms of mutant cells per 0.1 microM MNNG. On the contrary, MR10-1 cells (mer-) and two HeLa S3 mer+ cells lines differed in the induction of mutation as a function of MNNG concentration. The HeLa mer+ cell lines were not mutable, while MR10-1 cells were highly mutable. These above results clearly show that the HeLa mer- cell has at least two defects in the repair of the alkylated adducts which are related to cell killing and mutation, and also suggest that O6-MeG is involved in the induction of mutation.

UI MeSH Term Description Entries
D008769 Methylnitronitrosoguanidine A nitrosoguanidine derivative with potent mutagenic and carcinogenic properties. Methylnitrosonitroguanidine,Nitrosomethylnitroguanidine,Nitrosonitromethylguanidine,MNNG,N-Methyl-N'-nitro-N-nitrosoguanidine,N Methyl N' nitro N nitrosoguanidine
D008780 Methyltransferases A subclass of enzymes of the transferase class that catalyze the transfer of a methyl group from one compound to another. (Dorland, 28th ed) EC 2.1.1. Methyltransferase
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D004351 Drug Resistance Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration. Resistance, Drug
D006367 HeLa Cells The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for, among other things, VIRUS CULTIVATION and PRECLINICAL DRUG EVALUATION assays. Cell, HeLa,Cells, HeLa,HeLa Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000477 Alkylating Agents Highly reactive chemicals that introduce alkyl radicals into biologically active molecules and thereby prevent their proper functioning. Many are used as antineoplastic agents, but most are very toxic, with carcinogenic, mutagenic, teratogenic, and immunosuppressant actions. They have also been used as components in poison gases. Alkylating Agent,Alkylator,Alkylators,Agent, Alkylating,Agents, Alkylating
D019853 O(6)-Methylguanine-DNA Methyltransferase An enzyme that transfers methyl groups from O(6)-methylguanine, and other methylated moieties of DNA, to a cysteine residue in itself, thus repairing alkylated DNA in a single-step reaction. EC 2.1.1.63. Methylated-DNA-Protein-Cysteine S-Methyltransferase,O(6)-AGT,O(6)-Methylguanine Methyltransferase,DNA Repair Methyltransferase I,DNA Repair Methyltransferase II,Guanine-O(6)-Alkyltransferase,O(6)-Alkylguanine-DNA Alkyltransferase,O(6)-MeG-DNA Methyltransferase,O(6)-Methylguanine DNA Transmethylase,Methylated DNA Protein Cysteine S Methyltransferase,S-Methyltransferase, Methylated-DNA-Protein-Cysteine

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