Chromosome Breakage and Sensitivity to DNA Breaking Agents in Ataxia-Telangiectasia and their Possible Association with Predisposition to Cancer

  • Yechiel Becker
  • Meira Shaham
  • Yosef Shiloh
  • Ruth Voss
Part of the NATO Advanced Science Institutes Series book series (NSSA, volume 57)


Ataxia-telangiectasia (A-T) is an autosomal recessive disease characterized by increased spontaneous chromosomal breakage and a predisposition to cancer in both A-T patients and their heterozygous relatives. We have demonstrated the presence of a clastogenic factor in plasma of A-T patients, in medium conditioned by A-T fibroblasts, and in amniotic fluid of an affected A-T fetus. Our A-T fibroblast strains were found to be as sensitive as normal strains to the cytotoxic effect of methylating carcinogens. We confirmed their hypersensitivity to ionizing radiation and found that they were also markedly sensitive to treatment with the antitumor antibiotic neocarzinostatin. Two A-T heterozygote strains had intermediate sensitivity to neocarzinostatin which was distinct from that of the homozygote and the normal cells. The intrinsic hypersensitivity to DNA-breaking agents, coupled with the presence of a clastogenic factor, may account for the high rate of chromosomal breakage in vivo and the predisposition to cancer.


Conditioned Medium Amniotic Fluid Chromosome Breakage Autosomal Recessive Disease Methyl Methane Sulfonate 


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  1. Beerman, T.A. and Goldberg, I.H., 1974, DNA strand scission by the antitumor protein neocarzinostatin, Biochem. Biophys. Res. Commun., 59: 1254.CrossRefGoogle Scholar
  2. Cohen, M.M., Shaham, M., Dagan, J., Shmuelli, E. and Kohn, G., 1975, Cytogenetic investigations in families with ataxia-telangiectasia, Cytogenet. Cell Genet. 15: 338.CrossRefGoogle Scholar
  3. Cramer, P. and Painter, R.B., 1981, Bleomycin-resistant DNA synthesis in ataxia-telangiectasia cells, Nature, 291: 671.CrossRefGoogle Scholar
  4. Cunliffe, P.N., Mann, J.R., Cameron, A.H. and Roberts, K.D., 1975, Radiosensitivity in ataxia-telangiectasia, Br. J. Radiol., 48: 374.CrossRefGoogle Scholar
  5. Edwards, M.J. and Taylor, A.M.R., 1980, Unusual levels of ( ADP- ribose)n and DNA synthesis in ataxia-telangiectasia cells following X-ray irradiation, Nature, 287: 745.CrossRefGoogle Scholar
  6. Emerit, E. and Cerutti, P., 1981, Clastogenic activity from Bloom’s syndrome fibroblast cultures, Proc. Natl. Acad. Sci. USA, 78: 1868.CrossRefGoogle Scholar
  7. Gotoff, S.P., Amirmokro, E. and Liebner, E.J., 1967, Ataxia-telangiectasia. Neoplasia, untoward response to X-irradiation and tuberous sclerosis, Amer. J. Pis. Child, 114: 617.Google Scholar
  8. Hayward, W.S., Neel, B.G. and Astrin, S.M., 1981, Activation of a cellular one gene by promoter insertion in ALV-induced lymphoid leukosis, Nature 290: 475.CrossRefGoogle Scholar
  9. Hecht, F. and McCaw, B.K., 1977, Chromosome instability syndrome, Progr. Cancer Res. Ther., 3: 105.Google Scholar
  10. Hoar, D.I. and Sargent, P., 1976, Chemical mutagen hypersensitivity in ataxia telangiectasia, Nature, 261: 590.CrossRefGoogle Scholar
  11. Lehmann, A.R. and Stevens, S., 1977, The production and repair of double-strand breaks in cells from normal humans and from patients with ataxia-telangiectasia. Biochim. Biophys Acta 474: 49.CrossRefGoogle Scholar
  12. Lehmann, A.R. and Stevens, S., 1979, The response of ataxia-telangiectasia cells to bleomycin, Nucleic Acids Res. 6: 1953.CrossRefGoogle Scholar
  13. McCaw, B.K., Hecht, F., Harnden, D.G. and Teplitz, R.L., 1975, Somatic rearrangement of chromosome 14 in human lymphocytes, Proc. Natl. Acad. Sci. USA, 72: 2071.CrossRefGoogle Scholar
  14. McFarlin, D.E., Strober, W., and Waldmann, T.A., 1972, Ataxia-telangiectasia. Medicine 51: 281.CrossRefGoogle Scholar
  15. Morgan, J.L., Holcomb, T.M. and Morrissey, R.W., 1968, Radiation reaction in ataxia telangiectasia, Am. J. Dis. Child 116: 557.Google Scholar
  16. Painter, R.B., and Young, B.R., 1980, Radiosensitivity in ataxia- telangiectasia: a new explanation, Proc. Natl. Acad. Sci. USA 77: 7315.CrossRefGoogle Scholar
  17. Paterson, M.C., Anderson, A.K., Smith, B.P. and Smith, P.J., 1979, Enhanced radiosensitivity of cultured fibroblasts from ataxia-telangiectasia heterozygotes manifested by defective colony- forming ability and reduced PNA repair replication after hypoxic X-irradiation, Cancer Res. 39: 3725.Google Scholar
  18. Paterson, M.C., Smith, B.P., Lohman, P.H.M., Anderson, A.K. and Fishman, L., 1976, Pefective excision repair of X-ray damaged PNA in human (ataxia-telangiectasia) fibroblasts. Nature 260: 444.CrossRefGoogle Scholar
  19. Paterson, M.C. and Smith, P.J., 1979, Ataxia-telangiectasia. An inherited human disorder involving hypersensitivity to ionizing radiation and related PNA damaging chemicals. Ann. Rev. Genet. 13: 291.CrossRefGoogle Scholar
  20. Sarma, P.S.R., Pazalakshmi, S. and Samy, T.S.A., 1976, Studies on the interaction of neocarzinostatin with rat liver PNA in vivo and in vitro, Biochem. Pharmacol., 25: 789.CrossRefGoogle Scholar
  21. Scudiero, P.A., 1980, Pecreased PNA repair synthesis and defective colony-forming ability of ataxia-telangiectasia fibroblast cell strains treated with N-methyl-Nf-nitro-N-nitroso-guanidine, Cancer Res., 40: 984.Google Scholar
  22. Shaham, M. and Becker, Y., 1981, The ataxia-telangiectasia factor is a low molecular weight peptide, Human Genet, 58: 422.CrossRefGoogle Scholar
  23. Shaham, M., Becker, Y. and Cohen, M.M., 1980, A diffusable clastogenic factor in ataxia telangiectasia, Cytogenet. Cell Genet. 27: 155.CrossRefGoogle Scholar
  24. Shaham, Kohn, G,, Yarkoni, S., Becker., Y. and Voss, R., 1981, Prenatal diagnosis of ataxia-telangiectasia in cell-free amniotic fluid, J. Pediat. (in press).Google Scholar
  25. Sheridan, R.B., and Huang, P.C., 1979, Ataxia-telangiectasia:further considerations of the evidence for single-strand break repair, Mutation Res., 61: 415.CrossRefGoogle Scholar
  26. Shiloh, Y. and Becker, Y., 1981a, Ataxia-telangiectasia lympho-blastoid cell lines resemble non-A-T cell lines in their ability to remove MNNG-induced purine methylation adducts, in: “Ataxia- telangiectasia: A Cellular and Molecular Link Between Cancer, Neuropathology and Immune Deficiency”, B.A. Bridges and D.G. Harnden, Eds., John Wiley and Sons, London (in press).Google Scholar
  27. Shiloh, Y. and Becker, Y., 1981b, Kinetics of 06-methylguanine repair in human normal and ataxia-telangiectasia cell lines, and correlation of repair capacity with cellular sensitivity to methylating agents, Cancer Res, (in press).Google Scholar
  28. Shiloh, Y., Cohen, M.M. and Becker, Y., 1981a, Ataxia-telangiectasia: studies on DNA repair synthesis in fibroblast strains, in: “Chromosome Damage and Repair”, K. Kleppe and E. Seeberg, Eds., NATO/EMBO Advanced Studies Institute, Bergen, Norway, 1980, Plenum Press, New York (in press).Google Scholar
  29. Shiloh, Y., Tabor, E. and Becker, Y., 1981b, Cellular hypersensitivity to neocarzinostatin in ataxia-telangiectasia sk in fibroblastsGoogle Scholar
  30. Swift, L., Sholman, L., Perry, M. and Chase, C., 1976, Malignant neoplasms in the families of patients with ataxia-telangiectasia, Cancer Res. 36: 209.Google Scholar
  31. Taylor, A.M.R., Harnden, D.G., Arlett, C.F., Harcourt, S.A., Lehmann, A.R., Stevens, S. and Bridges, B.A., 1975, Ataxia-telangiectasia: a human mutation with abnormal radiation sensitivity, Nature 258: 427.CrossRefGoogle Scholar
  32. Taylor, A.M.R., Rosney, C.M. and Campbell, J.B., 1979, Unusual sensitivity of ataxia-telangiectasia cells to bleomycin, Cancer Res. 39: 1046.Google Scholar
  33. Vincent, R.A., Sheridan, R.B. and Huang, P.C., 1975, DNA strand breakage and repair in ataxia-telangiectasia fibroblast-like cells, Mutation Res. 33: 357.CrossRefGoogle Scholar
  34. Weichselbaum, R.R., Nove, J. and Little, J.B., 1980, X-ray sensitivity of fifty-three human diploid fibroblast cell strains from patients with characterized genetic disorders, Cancer Res. 40: 920.Google Scholar

Copyright information

© Springer Science+Business Media New York 1983

Authors and Affiliations

  • Yechiel Becker
    • 1
  • Meira Shaham
    • 1
  • Yosef Shiloh
    • 1
  • Ruth Voss
    • 1
  1. 1.Departments of Molecular Virology and Human GeneticsThe Hebrew University-Hadassah Medical CenterJerusalemIsrael

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