Hypersensitivity to cell killing and faulty repair of 1-beta-D-arabinofuranosylcytosine-detectable sites in human (ataxia-telangiectasia) fibroblasts treated with 4-nitroquinoline 1-oxide.
Dermal fibroblast strains from ataxia-telangiectasia (A-T) patients and clinically normal subjects were exposed to 4-nitroquinoline 1-oxide (4NQO) or its 3-methyl derivative (3me4NQO), and their colony-forming abilities and DNA metabolic properties were compared. Three A-T strains, i.e., AT2BE and AT3BI representing genetic complementation group AB and AT4BI belonging to group C, displayed enhanced (2.4- to 2.8-fold) sensitivity to reproductive inactivation by 4NQO, but exhibited normal survival in response to 3me4NQO. The initial induction and subsequent enzymatic repair of alkali-labile lesions (i.e., damaged sites converted to single-strand breaks in alkali) were quantitated by conventional velocity sedimentation analysis of cellular DNA in alkaline sucrose gradients. On exposure to concentrations of each chemical that produced comparable amounts of DNA damage, A-T and normal cells removed alkali-labile lesions at similar rates. However, the three 4NQO-sensitive A-T strains appeared to be defective in acting on alkali-stable adducts (formed by the parent compound but not its derivative), as judged by strand-break accumulation during posttreatment incubation with 1-beta-D-arabinofuranosylcytosine (araC). Specifically, the number of araC-detectable sites repaired in these A-T strains during the critical 2-h period immediately following 4NQO treatment ranged from 40 to 60% of that processed by normal controls. AT5BI, a fourth A-T strain assigned to complementation group D, responded normally to 4NQO-induced cytotoxicity and removed both alkali-labile and alkali-stable (araC-detectable) lesions normally. We thus conclude that the hypersensitivity of AT2BE, AT3BI, and AT4BI strains to 4NQO may be attributed, at least in part, to faulty execution of the excision-repair process operative on alkali-stable 4NQO adducts.
Mirzayans
R
R
Molecular Genetics and Carcinogenesis Laboratory, Cross Cancer Institute, Edmonton, Alberta, Canada.
Smith
B P
BP
Paterson
M C
MC
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity* / Q000031:analogs & derivatives; D001260:Ataxia Telangiectasia / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D005816:Genetic Complementation Test; D006801:Humans; D066298:In Vitro Techniques; D009600:Nitroquinolines / Q000633:toxicity*
D009600:Nitroquinolines; D003561:Cytarabine; C036910:3-methyl-4-nitroquinoline 1-oxide; D015112:4-Nitroquinoline-1-oxide; D004247:DNA