Correction of Post-γ Ray DNA Repair Deficiency in Ataxia-Telangiectasia Complementation Group A Fibroblasts by Cocultivation with Normal Fibroblasts
Ataxia-telangiectasia (A-T) is a rare human recessively-inherited disorder characterized by, among other symptoms, a devastating and sometimes fatal reaction to conventional radiotherapy (Boder, 1985; Sedgwick and Boder, 1991). Radiation intolerance in vitro, as manifested by impaired colony-forming ability and exessive chromosomal instability, is universally displayed by cultured dermal fibroblasts and peripheral blood lymphocytes derived from A-T donors (Lehmann, 1982; Taylor, 1982; Paterson et al, 1984). As an extension of these radiobiological studies on A-T, we have recently conducted a detailed study on the deleterious effects of 4-nitroquinoline 1-oxide (4NQO), a partially radiomimetic carcinogen, on A-T fibroblast strains and have demonstrated that representative strains belonging to complementation groups A (AT2BE and AT3BI) and C (AT4BI) are defective in removal of a class of alkali-stable 4NQO-DNA adducts, whereas a group D strain (AT5BI) exhibits normal repair capacity (Mirzayans et al, 1989; Mirzayans and Paterson, 1991a). In this investigation, repair was monitored with the aid of 1-β-D-arabinofuranosylcytosine (araC), a potent inhibitor of DNA polymerases α and δ (Wist, 1979; Cleaver, 1984; Keeney and Linn, 1990). In this widely used approach, the extent of DNA strand breaks accumulating in cultures incubated with araC, following carcinogen treatment, becomes a measure of the efficiency to perform long-patch excision repair (Snyder et al., 1984; Cleaver, 1989; Mirzayans and Paterson, 1991b).
KeywordsNormal Fibroblast Normal Human Fibroblast GM38 Cell Fibroblast Strain Phospholipid Dependent Protein Kinase
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- Boder E (1985) Ataxia-telangiectasia: An overview. In: RA Gatti and M Swift (eds) Ataxia-Telangiectasia: Genetics, Neuropathology and Immunology of a Degenerative Disease of Childhood. pp. 1–63, Liss, New YorkGoogle Scholar
- Catagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U and Nishizuka Y (1982) Direct activation of calcium-activated phospholipid dependent protein kinase by tumour promoting phorbol esters. J Biol Chem 257:7847–7851Google Scholar
- Fricke H and Hart EJ (1966) Chemical dosimetry. In: Attix EH and Roesch EJ (eds) Radiation Dosimetry, Vol. 2, 2nd ed., pp. 167–239, Academic Press, New YorkGoogle Scholar
- Lehmann AR (1982) The cellular and molecular responses of ataxia-telangiectasia cells to DNA damage. In: Bridges BA and Harnden DG (eds) Ataxia-Telangiectasia — A Cellular and Molecular Link Between Cancer, Neuropathology, and Immune Deficiency, pp. 83–101, Wiley, ChichesterGoogle Scholar
- Mirzayans R, Smith BP and Paterson MC (1989) Hypersensitivity to cell killing and faulty repair of 1-β-D-arabinofuranosylcytosine-detectable sites in ataxia-telangiectasia fibroblasts treated with 4-nitroquinoline 1-oxide. Cancer Res: 5523–5529Google Scholar
- Paterson MC, Bech-Hansen NT, Smith PJ and Mulvihill JJ (1984) Radiogenic neoplasia, cellular radiosensitivity, and faulty DNA repair. In: Boice JD Jr and Fraumeni JF Jr. (eds) Radiation Carcinogenesis: Epidemiology and Biological Significance, pp. 319–336, New York: Raven PressGoogle Scholar
- Paterson MC, Aubin RA, Fourney RM and Mirzayans R (1989) Survey of post-y ray colony-forming ability, DNA metabolism and oncogene status in nonmalignant fibroblast strains from cancer-prone families and individual cancer patients. In: Baverstock KF and Stather JW (eds) 14th L.H. Grey Conference on Low ose Radiation Risk Assessment, pp. 227–239, Taylor & Francis, LondonGoogle Scholar
- Sedgwick RP and Boder E Ataxia-Telagiectasia (1991) In: de Jong JMBV (ed) Handbook of Clinical Neurology: Hereditary Neuropathies and Spinocellular Atrophies. Vol. 16(60), pp. 347–423, Elsevier Science Publ., AmesterdamGoogle Scholar
- Snyder RD, Van Houten B and Regan JD (1984) The accumulation of DNA breaks due to incision; comparative studies with various inhibitors. In: Collins A, Downes CS and Johnson RT (eds) DNA Repair and Its Inhibition, pp. 13–43, IRL Press, Oxford, EnglandGoogle Scholar
- Taylor AMR (1982) Cytogenetics of ataxia-telangiectasia. In: Bridges BA and Harnden DG (eds) Ataxia-Telangiectasia — A Cellular and Molecular Link Between Cancer, Neuropathology, and Immune Deficiency, pp. 53–81, Wiley, ChichesterGoogle Scholar