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Ataxia-Telangiectasia: Defective in a P53-Dependent Signal Transduction Pathway

  • Michael B. Kastan
Conference paper
Part of the NATO ASI Series book series (volume 77)

Abstract

Damage to DNA in proliferating cells results in alterations of progression through the cell cycle (e.g. Tolmach et al, 1977; Painter and Young, 1980; Lau and Pardee, 1982; Weinert and Hartwell, 1988; Kaufmann et al, 1991; O’Connor et al, 1992). Such cell cycle “checkpoints” appear to be active cellular responses which permit optimal repair of DNA damage so that the cell will not replicate a damaged DNA template (G1 arrest) nor segregate damaged chromosomes (G2 arrest). Defects in these checkpoints are thought to contribute to decreased cell survival and increased propagatable genetic abnormalities following DNA damage (Hartwell and Weinert, 1989). One consequence of failing to repair DNA damage prior to replicative DNA synthesis is that mutagenic lesions could be fixed and propagated and could thus contribute to the genomic changes which result in neoplastic transformation. Abnormalities in the RAD9 gene in yeast result in a defect in the G2 arrest following ionizing irradiation — such mutant yeast exhibit increased sensitivity and increased genetic abnormalities following exposure to ionizing radiation (Weinert and Hartwell, 1988; Hartwell and Weinert, 1989). However, little has been clarified about the molecular and genetic controls of these checkpoints in mammalian cells.

Keywords

Cell Cycle Checkpoint Ataxia Telangiectasia Nijmegen Breakage Syndrome GADD45 Gene Diphosphate Ribose 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Doll, R. and Peto, R. (1981). The causes of cancer in the United States today. J.N.C.I. 66, 1192–1308.Google Scholar
  2. Donehower, L.A., Harvey, M., Slagle, B.L., McArthur, M.J., Montgomery C.A., Butel, J.S., and Bradley, A. (1992). Mice deficient for p53 are developmental normal but susceptible to spontaneous tumours. Nature 356, 215–221.PubMedCrossRefGoogle Scholar
  3. Gatti, R.A., Boder, E., Vinters, H.V., Sparkes, R.S., Norman, A., and Lange, K. (1991). Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis. Medicine 70, 99–117.PubMedCrossRefGoogle Scholar
  4. Hartwell, L.H. and Weinert, T.A (1989) Checkpoints: Controls that ensure the order of cell cycle events. Science 246, 629–634.PubMedCrossRefGoogle Scholar
  5. Hecht, F. and Hecht, B.K. (1990). Cancer in Ataxia-telangiectasia patients. Cancer Genet. Cytogenet. 46, 9–19.PubMedCrossRefGoogle Scholar
  6. Hollstein, M., Sidransky, D., Vogelstein, B., and Harris, C.C. (1991). p53 mutations in human cancers. Science 253, 49–53.PubMedCrossRefGoogle Scholar
  7. James, M.R. and Lehmann, AR. (1982). Role of poly(adenosine diphosphate ribose) in deoxyribonucleic acid repair in human fibroblasts. Biochemistry 21, 4007–4013.PubMedCrossRefGoogle Scholar
  8. Jaspers, N.G.J., Gatti, R.A., Baan, C, Linssen, P.C.M.L., and Bootsma, D. (1988).Google Scholar
  9. Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet. Cell. Genet. 49, 259–263.Google Scholar
  10. Kapp, L.N., and Painter, R.B. (1989). Stable radioresistance in ataxia-telangiectasia cells containing DNA from normal human cells. Int. J. Radiat. Biol. 56, 661–675.CrossRefGoogle Scholar
  11. Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B., and Craig, R. W. (1991). Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51, 6304–6311.PubMedGoogle Scholar
  12. Kastan, M.B., Zhan, Q., El-Deiry, W.S., Carrier, F., Jacks, T., Walsh, W.V., Plunkett, B.S., Vogelstein, B., and Fornace, A.J., Jr. (1992). A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia telangiectasia. Cell 71, 587–597.PubMedCrossRefGoogle Scholar
  13. Kaufmann, W.K., Boyer, J.C., Estabrooks, L.L., and Wilson, S.J. (1991). Inhibition of replicon initiation in human cells following stabilization of topoisomerase -DNA cleavable complexes. Mol. Cell. Biol. 11, 3711–3718.PubMedGoogle Scholar
  14. Kuerbitz, S. J., Plunkett, B. S., Walsh, W. V., and Kastan, M. B. (1992). Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc. Natl. Acad. Sci. USA 89, 7491–7495.PubMedCrossRefGoogle Scholar
  15. Lambert, C., Schultz, R.A., Smith, M., Wagner-McPherson, C., McDaniel, D., Donlon, T., Stanbridge, E.J., and Friedberg, E.C. (1991). Functional complementation of ataxia-telangiectasia group D (AT-D) cells by microcell -mediated chromosome transfer and mapping of the AT-D locus to the region 11q22–23. Proc. Natl. Acad. Sci. USA 88, 5907–5911.PubMedCrossRefGoogle Scholar
  16. Lau, C.C. and Pardee, A.B. (1982). Mechanism by which caffeine potentiates lethality of nitrogen mustard. Proc. Natl. Acad. Sci. 79, 2942–2946.PubMedCrossRefGoogle Scholar
  17. Lehman, A.R., Arlett, C.F., Burke, J.F., Green, M.H.L., James, M.R., and Lowe, J.E. (1986). A derivative of an ataxia-telangiectasia (A-T) cell line with normal radiosensitivity but A-T-like inhibition of DNA synthesis. Int, J. Radiat. Biol. 49, 639–643.CrossRefGoogle Scholar
  18. Malkin, D., Li, F.P., Strong, L.C., Fraumeni, J.F., Jr., Nelson, C.E., Kim, D.H., Kassel, J., Gryka, M.A., Bischoff, F.Z., Tainsky, M.A., and Friend, S.H. (1990). Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238.PubMedCrossRefGoogle Scholar
  19. McKinnon, P.J. (1987). Ataxia-telangiectasia: an inherited disorder of ionizing -radiation sensitivity in man. Hum. Genet. 75, 197–208.PubMedCrossRefGoogle Scholar
  20. Morrell, D., Cromartie, E., and Swift, M. (1986). Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J. Natl. Cancer Inst. 77, 89–92.PubMedGoogle Scholar
  21. Nagasawa, H., Latt, S.A., Lalande, M.E., and Little, J.B. (1985). Effects of x-irradiation on cell-cycle progression, induction of chromosomal aberrations and cell killing in ataxia telangiectasia (AT) fibroblasts. Mut. Res. 148, 71–82.CrossRefGoogle Scholar
  22. O’Connor. P.M., Ferris, D.K., White, G.A., Pines, J., Hunter, T., Longo, D.L., and Kohn, K.W. (1992). Relationships between cdc2 kinase, DNA cross-linking, and cell cycle perturbations induced by nitrogen mustard. Cell Growth and Diff. 3, 43–52.Google Scholar
  23. Painter, R.B. and Young, B.R. (1980). Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc. Natl. Acad. Sci. USA. 77, 7315–7317.PubMedCrossRefGoogle Scholar
  24. Painter, R.B. (1985). 3-Aminobenzamide does not affect radiation-induced inhibition of DNA synthesis in human cells. Mut. Res. 143, 113–115.CrossRefGoogle Scholar
  25. Papathanasiou, M. A., Kerr, N. C., Robbins, J. H., McBride, O. W., Alamo, I. J., Barrett, S. F., Hickson, I. D., and Fornace, A. J. Jr. (1991). Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C. Mol Cell Biol 11, 1009–1016.PubMedGoogle Scholar
  26. Rudolph, N.S. and Latt, S.A. (1989). Flow cytometric analysis of x-ray sensitivity in ataxia-telangiectasia. Mut. Res. 211, 31–41.CrossRefGoogle Scholar
  27. Satoh, M.S. and Lindahl, T. (1992). Role of poly(ADP-ribose) formation in DNA repair. Nature 356, 356–358.PubMedCrossRefGoogle Scholar
  28. Solomon, E., Borrow, J., and Goddard, A.D. (1991). Chromosome aberrations and cancer. 254, 1153–1160.Google Scholar
  29. Srivasta, S., Zou, Z., Pirollo, K., Blattner, W., and Chang, E.H. (1990). Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 348, 747–749.CrossRefGoogle Scholar
  30. Sullivan, N. and Lyne, L. (1990). Sensitivity of fibroblasts derived from ataxia-telangiectasia patients to calicheamicin γ 1Mut. Res. 245, 171–175.CrossRefGoogle Scholar
  31. Swift, M., Reitnauer, P.J., Morrell, D., and Chase, C.L. (1987). Breast and other cancers in families with ataxia-telangiectasia. N. Engl. J. Med. 316, 1289–1294.PubMedCrossRefGoogle Scholar
  32. Swift, M., Morrell, D., Massey, R.B., and Chase, C.L. (1991). Incidence of cancer in 161 families affected by ataxia-telangiectasia. N. Engl. J. Med. 325, 1831–1836.PubMedCrossRefGoogle Scholar
  33. Tolmach, L.J., Jones, R.W., and Busse, P.M. (1977). The action of caffeine on X-irradiated HeLa cells. I. Delayed inhibition of DNA synthesis. Rad. Res. 71, 653–665.CrossRefGoogle Scholar
  34. Vogelstein, B. (1990). A deadly inheritance. Nature 348, 681–682.PubMedCrossRefGoogle Scholar
  35. Walters, R.A., Gurley, L.R., and Tobey, R.A. (1974). Effects of caffeine on radiation-induced phenomena associated with cell-cycle traverse of mammalian cells. Biophys. J. 14, 99–118.PubMedCrossRefGoogle Scholar
  36. Weinert, T.A. and Hartwell, L.H. (1988). The RAD9 gene controls the cell cycle response to DNA damage in saccharomyces cerevisiae. Science 241. 317–322.PubMedCrossRefGoogle Scholar
  37. Weinert, T.A. and Hartwell, L.H. (1990). Characterization of RAD9 of saccharomyces cerevisiae and evidence that its function acts posttranslationally in cell cycle arrest after DNA damage. Mol. Cell. Biol. 10, 6554–6564.PubMedGoogle Scholar
  38. Zampetti-Bosseler, F. and 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. 39, 547–558.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • Michael B. Kastan
    • 1
  1. 1.Department of OncologyJohns Hopkins University School of MedicineBaltimoreUSA

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