title: Defective mismatch binding and a mutator phenotype in cells tolerant to DNA damage.
abstract: Acquired resistance to alkylating agents such as N-methyl-N-nitrosourea or N-methyl-N'-nitro-N-nitrosoguanidine results from the ability to tolerate the potentially cytotoxic methylated base O6-methylguanine (m6-G) in DNA. In the absence of repair by demethylation in situ, m6-G is probably lethal through its inappropriate processing by the cell. DNA mismatch correction is an attractive candidate for the processing function because although it is replicated, m6-G has no perfect complementary base. Thus, m6-G in DNA might provoke abortive mismatch repair and tolerance could subsequently arise through loss of a mismatch repair pathway. Mismatch correction helps maintain genomic fidelity by removing misincorporated bases and deaminated 5-methylcytosine from DNA, and its loss by mutation confers a mutator phenotype on Escherichia coli. Here we describe human and hamster cell lines that are tolerant to N-methyl-N-nitrosourea and are defective in a DNA mismatch binding activity. The loss of this activity, which acts on G.T mispairs, confers a mutator phenotype.
authors: Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms, Herts, UK.
authors: P
authors: P
authors: Branch
authors: G
authors: G
authors: Aquilina
authors: M
authors: M
authors: Bignami
authors: P
authors: P
authors: Karran
mesh_terms: D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D004249:DNA Damage; D004260:DNA Repair; D004351:Drug Resistance; D006151:Guanosine / Q000378:metabolism; D006801:Humans; D008745:Methylation; D008770:Methylnitrosourea / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D009692:Nucleic Acid Heteroduplexes; D009838:Oligodeoxyribonucleotides; D010641:Phenotype; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D009692:Nucleic Acid Heteroduplexes; D009838:Oligodeoxyribonucleotides; D006151:Guanosine; D008770:Methylnitrosourea; D013936:Thymidine