title: Kinetics of O6-methylguanine repair in human normal and ataxia telangiectasia cell lines and correlation of repair capacity with cellular sensitivity to methylating agents.
abstract: Human lymphoblastoid cell lines from normal individuals and from patients with ataxia telangiectasia were either proficient or deficient in their ability to repair the mutagenic DNA adduct O6-methylguanine that is induced by methylating carcinogens. There was no relationship between the capacity to repair O6-methylguanine and the ataxia telangiectasia phenotype. Time-course studies done following a short pulse (2 min) of alkylation with 0.5 microgram of N-[3H]methyl-N'-nitro-N-nitrosguanidine per ml revealed that the repair of O6-methylguanine in human lymphoblastoid lines proficient in this ability is a rapid process, which proceeds with a half-life of 10 to 15 min. Lymphoblastoid lines with deficient capacity to repair this DNA adduct were hypersensitive to the cytotoxic effect of the methylating carcinogens N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosourea, and methyl methanesulfonate, and this hypersensitivity was correlated with the relative amount of O6-methylguanine induced by each of the three chemicals. This was taken as an indication of the lethality of unrepaired O6-methylgluanine. The extent of DNA repair synthesis induced by the three carcinogens was the same in cell lines proficient and deficient in O6-methylguanine repair, indicating no major deficiency in an excision repair pathway in the hypersensitive cell lines.
mesh_terms: D000293:Adolescent; D000328:Adult; D000477:Alkylating Agents / Q000494:pharmacology*; D001260:Ataxia Telangiectasia / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007700:Kinetics; D008297:Male; D008741:Methyl Methanesulfonate; D008745:Methylation; D008769:Methylnitronitrosoguanidine; D008770:Methylnitrosourea
chemical_list: D000477:Alkylating Agents; D008769:Methylnitronitrosoguanidine; D006147:Guanine; D008770:Methylnitrosourea; D004247:DNA; C008449:O-(6)-methylguanine; D008741:Methyl Methanesulfonate