Radiobiology of Ataxia-Telangiectasia

  • Robert B. Painter
Part of the NATO ASI Series book series (volume 77)

Abstract

The discovery that ataxia-telangiectasia (A-T) patients (Morgan et al., 1968; Gotoff et al., 1967; Cunliffe et al., 1975), as well as cells from these patients (Taylor et al., 1975), are hypersensitive to ionizing radiation (Fig. 1) has sparked an outpouring of research aimed at determining the basis of this radiosensitivity and its relationship to the pathology of the disease. The increased susceptibility of A-T cells to killing by ionizing radiation can largely be correlated with the increased frequency of radiation-induced chromosomal aberrations (Bender et al., 1985, 1988; Higurachi and Conen, 1973; Nagasawa et al., 1985; Natarajan and Meyers, 1979; Taylor, 1982; Zampetti-Bosseler and Scott, 1981); however, the molecular basis of this extraordinary radiosensitivity is still not understood. Many chromatid-type aberrations are observed after irradiation of A-T cells in the G1 phase of the cell cycle (Bender et al., 1985; Natarajan and Meyers, 1979; Taylor et al., 1976; Taylor, 1978), something almost never seen in normal cells or in cells from patients with other genetic diseases. This suggests that some kind of damage that is always repaired in normal cells before they move into S phase is not repaired in A-T cells. Unfortunately, this is a clue that no one has yet been able to exploit.

Keywords

Lymphoma Sedimentation Adenosine Diphosphate Ribose 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bender MA, Rary JM, Kale RP (1985) Go chromosomal sensitivity in ataxia telangiectasia lymphocytes. Mutat Res 150:277–282PubMedCrossRefGoogle Scholar
  2. Bender MA, Viola MV, Fiore J, Thompson MH, and Leonard RC (1988) Normal G2 chromosomal radiosensitivity and cell survival in the cancer family syndrome. Cancer Res 48:2579–2584PubMedGoogle Scholar
  3. Cleaver JE (1968) Defective repair replication of DNA in xeroderma pigmentosum. Nature 218: 652–656PubMedCrossRefGoogle Scholar
  4. Cox R, Masson WK, Weichselbaum RR, Nove J, Little JB (1981) The repair of potentially lethal damage in ataxia telangiectasia fibroblasts. Int J Radiat Biol 39:357–365CrossRefGoogle Scholar
  5. Cunliffe PN, Mann JR, Cameron AH, Roberts KD, and Ward HWC (1975) Radiosensitivity in ataxia telangiectasia. Br J Radiol 48:374–376CrossRefGoogle Scholar
  6. Ford MD, Martin L, Lavin MF (1984) The effects of ionizing radiation on cell cycle progression in ataxia telangiectasia. Mutat Res 125:115–124PubMedCrossRefGoogle Scholar
  7. Gotoff P, Amirmokri E, and Iiebner EJ (1967) Ataxia telangiectasia. Neoplasia, untoward response to x-irradiation, and tuberous sclerosis. Am J Dis Child 114:617–625PubMedGoogle Scholar
  8. Hall EJ (1973) Radiobiology for the radiologist. Harper & Row, Hagerstown, MarylandGoogle Scholar
  9. Higurachi M, Conen PE (1973) In vitro chromosomal radiosensitivity in “chromosomal breakage syndromes.” Cancer 32:380–383CrossRefGoogle Scholar
  10. Houldsworth J, Lavin MF (1980) Effect of ionizing radiation on DNA synthesis in ataxia telangiectasia cells. Nucl Acids Res 8:3709–3720PubMedCrossRefGoogle Scholar
  11. James MR, Lehmann AR (1982) Role of adenosine poly (adenosine diphosphate ribose) in deoxyribonucleic acid repair in human fibroblasts. Biochemistry 21: 4007–4013PubMedCrossRefGoogle Scholar
  12. Jaspers NGJ, Gatti RA, Baan C, Linssen PC, Bootsma D (1988) Genetic complementation analysis of ataxia telangiectasia and the Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet Cell Genet 49:259–263PubMedCrossRefGoogle Scholar
  13. Kapp LN, Painter RB (1989) Stable radioresistance in ataxia-telangiectasia cells-containing DNA from normal human cells. Int J Radiat Biol 56:667–675PubMedCrossRefGoogle Scholar
  14. Kapp LN, Painter RB, Yu L-C, van Loon N, Richard CW, III, James MR, Cox DR, Murnane JP (1992) Cloning of a candidate gene for ataxia-telangiectasia group D. Am J Hum Genet 51:45–54PubMedGoogle Scholar
  15. Lehmann AR, Jaspers NGJ, Gatti RA (1989) Fourth International Workshop on Ataxia-Telangiectasia (meeting report). Cancer Res 49:6162–6163PubMedGoogle Scholar
  16. Makino F, Okada S (1975) Effects of ionizing radiations on DNA replication in cultured mammalian cells. Radiat Res 62: 37–51PubMedCrossRefGoogle Scholar
  17. Morgan JL, Holcomb IM, Morrissey RW (1968) Radiation reaction in ataxia-telangiectasia. Am J Dis Child 116:557–558PubMedGoogle Scholar
  18. Nagasawa H, Latt SA, Lalande ME, and Little JB (1985) Effects of X-irradiation on cell cycle progression, induction of chromosomal aberrations and cell killing in ataxia telangiectasia (A-T) fibroblasts. Mutat Res 148:71–82PubMedCrossRefGoogle Scholar
  19. Natarajan A-T, Meyers M (1979) Chromosome radiosensitivity of ataxia telangiectasia cells at different cell stages. Hum Genet 52:127–132PubMedCrossRefGoogle Scholar
  20. Ockey CH (1983) Differences in replicon behavior between X-irradiation-sensitive mouse lymphoma cells and A-T fibroblasts using fiber autoradiography. Radiat Res 94: 427–438PubMedCrossRefGoogle Scholar
  21. Painter RB (1983) Are lesions induced by ionizing radiation direct blocks to DNA chain elongation? Radiat Res 95: 421–426PubMedCrossRefGoogle Scholar
  22. Painter RB (1985) 3-Aminobenzamide does not affect radiationinduced inhibition of DNA synthesis in human cells. Mutat Res 143: 113–115PubMedCrossRefGoogle Scholar
  23. Painter RB (1986) Inhibition of mammalian cell DNA synthesis by ionizing radiation. Int J Radiat Biol 49:771–781CrossRefGoogle Scholar
  24. Painter RB, Young BR (1976) Formation of nascent DNA molecules during inhibition of replicon initiation in mammalian cells. Biochim Biophys Acta 418:146–153PubMedGoogle Scholar
  25. Painter RB, Young BR (1980) Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc Natl Acad Sci USA 77: 7315–7317PubMedCrossRefGoogle Scholar
  26. Pandita TK, Hittelman WN (1992) The contribution of DNA and chromosome repair deficiencies to the radiosensitivity of ataxia-telangiectasia. Radiation Res 131, in pressGoogle Scholar
  27. Scott D, Zampetti-Bosseler F (1982) Cell cycle dependence of mitotic delay in x-irradiated normal and ataxia-telangiectasis fibroblasts. Int J Radiat Biol 42: 679–683CrossRefGoogle Scholar
  28. Sikpi MO, Freedman ML, Dry SM, Lurie AG (1992) Mutation spectrum in γ-irradiated shuttle vector replicated in ataxia-telangiectasia lymphoblasts. Radiat Res 130: 331–339PubMedCrossRefGoogle Scholar
  29. Smith PJ, Paterson MC (1983) Effect of aphidicolin on de novo DNA synthesis, DNA repair and cytoxicity in γ-irradiated human fibroblasts: implications for the enhanced radiosensitivity in ataxia telangiectasia. Biochim Biophys Acta 739:17–26PubMedGoogle Scholar
  30. Swift M, Morrell D, Chamberlain AR, Skolnick MH, Bishop DT (1986) The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 39:573–583PubMedGoogle Scholar
  31. Swift M, Morrell D, Massey RB, Chase CL (1991) Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325:1831–1836PubMedCrossRefGoogle Scholar
  32. Taylor AMR (1978) Unrepaired DNA stand breaks in irradiated ataxia telangiectasia lymphocytes suggested from cytogenetic observations. Mutat Res 50:407–418PubMedCrossRefGoogle Scholar
  33. Taylor AMR (1982) Cytogenetics of ataxia telangiectasia. In BA Bridges and DG Harnden (eds). Ataxia telangiectasia — a cellular and molecular link between cancer, neuropathology and immune deficiency, pp 53–82. Chichester: WileyGoogle Scholar
  34. Taylor AMR, Harnden DG, Arlett CF, Harcourt SA, Lehmann AR, Stevens S, and Bridges BA (1975) Ataxia-telangiectasia: a human mutation with abnormal radiation sensitivity. Nature 258:427–429PubMedCrossRefGoogle Scholar
  35. Taylor AMR, Metcalfe JA, Oxford JM, and Harnden DG (1976) Is chromatid-type damage in ataxia telangiectasia after irradiation at GO a consequence of defective repair. Nature 260:441–443PubMedCrossRefGoogle Scholar
  36. Walters RA, Hildebrand CE (1975) Evidence that X-irradiation inhibits replicon initiation in Chinese hamster cells. Biochem Biophys Commun 65: 265–271CrossRefGoogle Scholar
  37. Zampetti-Bosseler F, Scott D (1981) Cell death, chromosome damage and mitotic delay in normal human, ataxia telangiectasia and retinoblastoma fibroblasts after X-irradiation. Int J Radiat Biol 49:485–494Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • Robert B. Painter
    • 1
  1. 1.Laboratory of Radiobiology and Environmental HealthUniversity of California, San FranciscoSan FranciscoUSA

Personalised recommendations