Correction of Post-γ Ray DNA Repair Deficiency in Ataxia-Telangiectasia Complementation Group A Fibroblasts by Cocultivation with Normal Fibroblasts

  • M. C. Paterson
  • R. Mirzayans
Conference paper
Part of the NATO ASI Series book series (volume 77)

Abstract

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).

Keywords

Neuropathy Glutamine Beach Thymidine Auger 

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References

  1. 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
  2. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziam A, Kapeller R and Soltoff S (1991) Oncogenes and signal transduction. Cell 64:281–302PubMedCrossRefGoogle Scholar
  3. 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
  4. Chang EH, Pirollo KF, Zou ZQ, Cheung H-Y, Lawler EL, Garner R, White E, Bernstein WB, Fraumeni JF Jr and Blattner WA (1987) Oncogenes in radioresistant, noncancerous skin fibroblasts from a cancer-prone family. Science 237:1036–1039PubMedCrossRefGoogle Scholar
  5. Cleaver JE (1984) Completion of excision repair patches in human cell preparations: identification of a probable mode of excision and resynthesis. Carcinogenesis 5:325–330PubMedCrossRefGoogle Scholar
  6. Cleaver JE (1989) DNA damage and repair in normal, xeroderma pigmentosum and XP revertant cells analysed by gel electrophoresis: excision of cyclobutane dimers from the whole genome is not necessary for cell survival. Carcinogenesis 10:1691–1696PubMedCrossRefGoogle Scholar
  7. 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
  8. Haimovitz-Friedman A, Vlodavsky I, Chaudhuri A, White L and Fuks Z (1991) Autocrine effects of fibroblast growth factor in repair of radiation damage in endothelial cells. Cancer Res 51:2552–2558PubMedGoogle Scholar
  9. Hiss, EA and Preston RJ (1977) The effect of cytosine arabinoside on the frequency of single-strand breaks in DNA of mammalian cells following irradiation or chemical treatment. Biochim Biophys Acta 478:1–8PubMedGoogle Scholar
  10. Kastan MB, Zhan Q, El-Deiry WS, Carrier F, Jacks T, Walsh V, Plunkett B, Vogelstein B and Fornace AJ Jr (1992) A mammalian cell cycle checkpoint pathway utilizing p53 and ADD45 is defective in ataxia-telangiectasia. Cell 71:587–597PubMedCrossRefGoogle Scholar
  11. Keeney S and Linn S (1990) A critical review of permeabilized cell systems for studying mammalian DNA repair. Mutat Res 236:239–252PubMedGoogle Scholar
  12. 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
  13. Marshall CJ (1991) Tumor suppressor genes. Cell 64:313–326PubMedCrossRefGoogle Scholar
  14. Mirzayans R and Paterson MC (1991a) Lack of correlation between hypersensitivity to cell killing and impaired inhibition of DNA synthesis in ataxia telangiectasia fibroblasts treated with 4-nitroquinoline 1-oxide. Carcinogenesis 12:19–24PubMedCrossRefGoogle Scholar
  15. Mirzayans R and Paterson MC (1991b) Differential repair of 1-β-D-arabinofuranosyl-cytosine-detectable sites in DNA of human fibroblasts exposed to ultraviolet light and 4-nitroquinoline 1-oxide. Mutat Res 255:57–65PubMedGoogle Scholar
  16. Mirzayans R, Waters R and Paterson MC (1988) Induction and repair of DNA strand breaks and 1-β-D-arabinofuranosylcytosine-detectable sites in 40–75 kVp X-irradiated compared to 60Co γ-irradiated human cell lines. Radiat Res 114:168–185PubMedCrossRefGoogle Scholar
  17. 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
  18. Mirzayans R, Andrais B and Paterson MC (1992) Synergistic effect of aphidicolin and 1-β-D-rabinofuranosylcytosine on the repair of y-ray-induced DNA damage in normal human fibroblasts. Int J Radiat Biol 62: 417–425PubMedCrossRefGoogle Scholar
  19. 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
  20. 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
  21. Schneider EL, Stanbridge EJ and Epstein CJ (1974) Incorporation of [3H]uridine and [3H]uracil into RNA: a simple technique for the detection of mycoplasma contamination of cultured cells. Exp Cell Res 84:311–318PubMedCrossRefGoogle Scholar
  22. 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
  23. 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
  24. Srivastava S, Zou Z, Pirollo K, Blattner W and Chang EH (1990) Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 348:747–749PubMedCrossRefGoogle Scholar
  25. 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
  26. Varmus HE (1984) The molecular genetics of cellular oncogenes. Ann Rev Genet 18: 553–612PubMedCrossRefGoogle Scholar
  27. Wang Y and Iliakis G (1992) Prolonged inhibition of DNA synthesis in cells obtained by transformation of primary rat embryo fibroblasts with oncogenes H-ras and v-myc. Cancer Res 52:508–514PubMedGoogle Scholar
  28. Weinberg RA (1985) The action of oncogenes in the cytoplasm and nucleus. Science 230:770–776PubMedCrossRefGoogle Scholar
  29. Wist E (1979) The role of DNA polymerases α, β and γ in nuclear DNA synthesis. Biochim Biophys Acta 562:62–69PubMedGoogle Scholar
  30. Xing Y, Connolly T, Futcher B and Beach D (1991) Human D-type cyclin. Cell 65:691–699CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • M. C. Paterson
    • 1
  • R. Mirzayans
    • 1
  1. 1.Molecular Oncology Program Department of MedicineCross Cancer InstituteEdmontonCanada

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