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5-Hydroxymethyluracil in Cellular DNA is Repaired and Sensitizes Cells to Inhibitors of Poly(ADP-Ribose) Synthesis

  • Robert J. Boorstein
  • Dan D. Levy
  • George W. Teebor

Abstract

5-Hydroxymethyluracil (HmUra) can be formed in DNA from thymidine by the action of ionizing radiation or by activated leukocytes (1–7). HmUra can be removed from DNA in vitro through the action of HmUra-DNA glycosylase (8,9) The repairability of HmUra suggests that it is deleterious to cells but the nature of its effects on cell function are uncertain. HmUra can also be introduced into cellular DNA as a result of the incorporation of the nucleoside, 5-hydroxymethy1–2’-deoxyuridine (HmdUrd) (10–12). HmUrd has been reported to be toxic to cells in culture and to animals (11,13,14) but the mechanism of this toxicity is unknown.

Keywords

Adenosine Diphosphate Ehrlich Ascites Carcinoma Cell L5178Y Cell Glycosylase Activity 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. 1.
    G. Scholes, The radiation chenistry of pyrimidines, purines and related substances. In Photochemistry and Photobiology of Nucleic Acids (S.Y. Wang, Ed.), Vol. I, pp. 521–577. Academic Press, New York, 1976.Google Scholar
  2. 2.
    J. G. Lewis and D. O. Adams, Induction of 5,6-ring-saturated thymine bases in NIH-3T3 cells by phorbol ester stimulated macrophages: Role of reactive oxygen intermediates. Cancer Res., 45, 1270–1275 (1985).PubMedGoogle Scholar
  3. 3.
    K. Frenkel, K. Chrzan, W. Troll, G. W. Teebor and J. J. Steinberg, Radiation-like modification of bases in DNA exposed to tumor promoter-activated polymorphonuclear leukocytes. Cancer Res., 46, 5533–5540 (1986).PubMedGoogle Scholar
  4. 4.
    P. A. Cerutti, Base damage induced by ionizing radiation. In Photochemistry and Photobiology of Nucleic Acids (S.Y. Wang, Ed), Vol. II, pp. 375–403. Academic Press, New York (1976)Google Scholar
  5. 5.
    H. L. Lewis, D. R. Muhleman, and J. F. Ward, Serologic assay of DNA base damage. I. 5-Hydroxymethyldeoxyuridine, a radiation product of thymidine. Radiant. Res., 75, 305–316 (1978).CrossRefGoogle Scholar
  6. 6.
    G. W. Teebor, K. Frenkel, and M. S. Goldstein, Ionizing radiation and tritium transmutation both cause formation of 5-hydroxymethy1–2’-deoxyuridine in cellular DNA. Proc. Natl. Acad. Sci. USA, 81, 318–321 (1984).PubMedCrossRefGoogle Scholar
  7. 7.
    K. Frenkel, A. Cummings, J. Solomon, J. Cadet, J. J. Steinberg, and G. W. Teebor, Quantitative determination of the 5-(Hydroxymethyl) uracil moiety in the DNA of gamma-irradiated cells. Biochemistry, 24, 4527–4533 (1985).PubMedCrossRefGoogle Scholar
  8. 8.
    M. C. Hollstein, P. Brooks, S. Linn, and B. N. Ames, Hydroxymethyluracil DNA glycosylase in namnalian cells. Proc. Natl. Acad. Sci. USA, 81, 4003–4007 (1984).PubMedCrossRefGoogle Scholar
  9. 9.
    R. J. Boorstein, D. D. Levy, and G. W. Teebor, 5-Hydroxymethyluracll-DNA glycosylase activity may be a differentiated function of mammalian cells. Proc. Natl. Res., 183, 257–263 (1987).Google Scholar
  10. 10.
    E. Matthes, D. Barwolff, and P. Langen, Altered DNA-protein interactions induced by 5-hydroxymethyldeoxyuridine in Ehrlich ascites carcinoma cells. Stud. Mophys., 67, 115–116 (1978).Google Scholar
  11. 11.
    L. I. Kesiaineini , E. Bergstrom, and J. A. Vilpo, 5-Hydroxymethyl-2’-deoxyuridine. Cytotoxicity and DNA incorporation studied by using a novel [2-14C]derivative with normal and leukemic human hematopoietic cells. Acta Chem. Scand. B, 39, 477–483 (1985).Google Scholar
  12. 12.
    E. R. Kaufman, BiochiSucal analysis of toxic effects of 5 hydroxymethyl-2’-deoxyuridine in mammalian cells. Somat. Cell Holec. Genet., 12, 501–512 (1986).CrossRefGoogle Scholar
  13. 13.
    S. Waschke, J. Reefschlager, D. Barwolff, and P. Langen, 5 Hydroxymethyl-2’-deoxyuridine, a nomal DNA constituent in certain Bacillus subtilis phages, is cytostatic for mammalian cells. Nature, 225, 629–630 (1975).CrossRefGoogle Scholar
  14. 14.
    J. B. Meldrum, V. S. Gupta, N. R. Lowes, and A. R. P. Paterson, Toxicologic and antitumor studies on 5-hydroxymethyldeoxyuridine. Toxicol. Appl. Pharmacol., 79, 423–435 (1985).PubMedCrossRefGoogle Scholar
  15. 15.
    N. Nduka, C. J. Skidmore, and S. Shall, The enhancement of cytotoxicity of N-methyl-N-nitrosourea and of ganaa-radiation by inhibitors of poly(ADP-ribose) polymerase. Eur. J. Biochem., 105, 525–530 (1980).Google Scholar
  16. 16.
    J. Lunec, A. M. George, M. Heges, W. A. Cramp, W. J. D. Whish, and B. Hunt, Post-irradiation sensitization with the ADP-ribosyltransferase in hibitor 3-acetanmdobenzamide. Br. J. Cancer, 49, Suppl. VI, 19–25 (1984).Google Scholar
  17. 17.
    I. Szumiel, D. Wlodek, K. J. Johnson, and S. Sundell-Bergman, ADP-ribosylation and post-irradiation recovery in two strains of L5178Y cells. Br. J. Cancer, 49, Suppl. VI, 33–38 (1984).Google Scholar
  18. 18.
    P. Thraves, K. L. Mossman, T. Brennan, and A. Dritschilo, Radiosensitization of human fibroblasts by 3-aminobenzamide: an inhibitor of poly(ADP-ribosylation). Radiate Res., 104, 119–127 (1985).CrossRefGoogle Scholar
  19. 19.
    A. M. Ueno, O. Tanaka, and H. Matsudaira, inhibition of gamma-ray dose-rate effects by D2O and inhibitors of poly(ADP-ribose) synthetase in cultured mammalian L5178Y cells. Radiat. Res., 98, 574–582 (1984).PubMedCrossRefGoogle Scholar
  20. 20.
    M. Purnell and W. J. D. Whish, Novel inhibitors of poly(ADP-ribose) synthetase. Biochem. J., 185, 775–777 (1980).PubMedGoogle Scholar
  21. 21.
    T. Lindahl, WortiSiy of à detour. Nature, 298, 424–425 (1982).PubMedCrossRefGoogle Scholar
  22. 22.
    T. Sugimura, and M. Miwa, Poly(ADP-ribose) and cancer research. Carcinogenesis, 4, 1503–1506 (1983).PubMedCrossRefGoogle Scholar
  23. 23.
    J. Lunec, Introductory review: involvement of ADP-ribosylation in cellular recovery from some forms of DNA damage. Br. J. Cancer, 49, Suppl. VI, 13–18, (1984).Google Scholar
  24. 24.
    N. E. Berger, Poly(ADP-ribose) in the cellular response to DNA damage. Radiat. Res., 101, 4–15, (1985).PubMedCrossRefGoogle Scholar
  25. 25.
    K. M. Milam and J. E. Cleaver, Inhibitors of poly (adenosine diphosphate-ribose) synthesis: Effect on other metabolic processes. Science, 233, 589–591, (1984).CrossRefGoogle Scholar
  26. 26.
    R. J. Boorstein and A. B. Pardee, Factors modifying 3-aminobenzamide cytotoxicity in normal and repair-deficient human fibroblasts. J. Cell Physiol., 120, 335–344, (1984).PubMedCrossRefGoogle Scholar
  27. 27.
    J. E. Cleaver, K. M. Milam, and W. F. Morgan, Do inhibitor studies demonstrate a role for poly(ADP-ribose) in DNA repair. Radiat. Res., 101, 16–28, (1985).PubMedCrossRefGoogle Scholar
  28. 28.
    D. I. Dugle, C. J. Gillespie, and J. D. Chapman, DNA strand breaks, repair and survival in x-irradiated mammalian cells. Proc. Natl. Acad. Sci USA, 73, 809–812, (1976).PubMedCrossRefGoogle Scholar
  29. 29.
    M. Gouilan, B. Bleile, and B. Y. Tseng, Methotrexate-induced misincorporâtion of uracil into DNA. Proc. Natl. Acad. Sci. USA, 77, 1956–1960, (1980).CrossRefGoogle Scholar
  30. 30.
    D. Criessen and S. Shall, Regulation of DNA ligase activity by poly(ADP-ribose). Nature, 296, 271–272 (1982).CrossRefGoogle Scholar
  31. 31.
    M. R. James and A. R. Lehmann, Role of Poly (adenosine diphosphate ribose) in deoxyribonucleic acid repair in human fibroblasts. Biochemistry, 21, 4007–4113, (1982).PubMedCrossRefGoogle Scholar
  32. 32.
    N. K. Kochetkov and E. I. Budovskii, Organic Chemistry of Nucleic Acids. Plenum Press, London, 1972.CrossRefGoogle Scholar
  33. 33.
    R. C. Benjamin and D. M. Gill, Poly(ADP-ribose) synthesis in vitro programmed by damaged DNA. J. Biol. Cheaa., 256, 10502–10508, (1980).Google Scholar
  34. 34.
    A. R. Lehmann and B. C. Broughton, Poly(ADP-ribosylation) reduces the steady-state level of breaks in DNA following treatment of human cells with alkylating agents. Carcinogenesis, 5, 117–119, (1984).PubMedCrossRefGoogle Scholar
  35. 35.
    N. L. Oleinick and H. N. Evans Poly(ADP-ribose) and the response of cells to ionizing radiation. Radiat. Res., 101, 29–46, (1985).PubMedCrossRefGoogle Scholar
  36. 36.
    E. Ben-Hur, H. Utsumi, and M. M. Elkind Inhibitors of poly (ADP-ribose) synthesis enhance radiation response by differentially affecting repair of potentially lethal damage. Br. J. Cancer, 49, Suppl. VI, 39–42, (1984).Google Scholar
  37. 37.
    D. M. Brown, J. W. Evans, and J. M. Brown, The influence of inhibitors of poly(ADF-ribose) polymerase on X-ray-induced potentially lethal damage repair. Br. J. Cancer, 49, Suppl. VI, 27–31, (1984).Google Scholar
  38. 38.
    R. B. Painter, Nonconseirvative Replication of Damaged DNA in Mammalian Cells. In Genetic Concepts and Neoplasia, pp. 593–599. Williams and Wilkins, Baltimore, 1970Google Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Robert J. Boorstein
    • 1
  • Dan D. Levy
    • 1
  • George W. Teebor
    • 1
  1. 1.Departments of Pathology and Environmental MedicineNew York University School of MedicineNew YorkUSA

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