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Hypersensitivity to Cell Killing and Faulty Repair of 1-ß-D-Arabinofuranosylcytosine-detectable Sites in Human (Ataxia-Telangiectasia) Fibroblasts Treated with 4-Nitroquinoline 1-Oxide¹

Molecular Genetics and Carcinogenesis Laboratory, Cross Cancer Institute, Edmonton, Alberta T6G 1Z2 [R. M., M. C. P.], and the Health Sciences Division, Chalk River Nuclear Laboratories, Chalk River, Ontario K0J 1J0 [B. P. S.], Canada

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-ß-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.

¹ Supported initially by Atomic Energy of Canada Limited and the U. S. National Cancer Institute through Contract NO1-CP-21029 (Basic) with the Clinical and Environmental Epidemiology Branches, Bethesda, MD, and in the later stages by research grants from the National Cancer Institute of Canada and the Ataxia-Telangiectasia Medical Research Foundation and by Medical Scientist (M. C. P.) and Postdoctoral Fellowship (R. M.) awards from the Alberta Heritage Foundation for Medical Research.

² To whom requests for reprints should be addressed, at Molecular Genetics and Carcinogensis Laboratory, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta T6G 1Z2, Canada.

Received 3/30/88. Revised 12/12/88. Revised 7/ 5/89. Accepted 7/ 6/89.

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