A Possible Role for Deoxyribonucleotide Pool Imbalances in Carcinogenesis

  • Robert H. Haynes
  • Bernard A. Kunz
Part of the Basic Life Sciences book series


Thymine nucleotide pool alterations, produced by attack on non-DNA primary targets, induce a variety of chromosome and chromatid aberrations. Specifically, in lower eukaryotes, thymidylate deprivation and excess are recombinagenic and dTMP depletion also produces DNA strand breakage. In higher eukaryotes, imbalances in thymine nucleotide pools provoke chromosome breaks and rearrangements, and inhibition of thymidylate biosynthesis causes morphological and oncogenic transformation in vitro. Thus, chromosomal rearrangements induced by dTMP deprivation may be the critical changes that lead to oncogenic transformation in response to thymine nucleotide depletion.


Chromosomal Rearrangement Sister Chromatid Exchange Fragile Site Oncogenic Transformation Mitotic Recombination 
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  1. Anderson, D., Richardson, C. R., and Davies, P. J., 1981, The genotoxic potential of bases and nucleosides, Mutat. Res., 91:265–272.PubMedCrossRefGoogle Scholar
  2. Ayusawa, D., Koyama, H., Iwata, K., and Seno, T., 1981, Selection of mammalian cell auxotrophic mutants defective in thymidylate synthetase by their reduced sensitivity to methotrexate, Somat. Cell Genet., 7:523–534.PubMedCrossRefGoogle Scholar
  3. Banerjee, A., and Benedict, W. F., 1979, Production of sister chromatid exchanges by various cancer chemotherapeutic agents, Cancer Res., 39:797–799.PubMedGoogle Scholar
  4. Barclay, B. J., Kunz, B. A., Little, J. G., and Haynes, R. H., 1982, Genetic and biochemical consequences of thymidylate stress, Can. J. Biochem., 60:172–194.PubMedCrossRefGoogle Scholar
  5. Benedict, W. F., Banerjee, A., Gardner, A., and Jones, P. A., 1976, Induction of morphological transformation in mouse C3H/10T½ clone 8 cells and chromosomal damage in hamster A(T1)C1–3 cells by cancer chemotherapeutic agents, Cancer Res., 37:2202–2208.Google Scholar
  6. Bjursell, G., and Reichard, P., 1973, Effects of thymidine on deoxy-ribonucleoside triphosphate pools and deoxyribonucleic acid synthesis in Chinese hamster ovary cells, J. Biol. Chem., 248:3904–3909.PubMedGoogle Scholar
  7. Blair, D. G., Oskarsson, M., Wood, T. G., McClements, W. L., Fischinger, P. J., and Vande Woude, G. G., 1981, Activation of the transforming potential of a normal cell sequence: a molecular model for oncogenesis, Science, 212:941–943.PubMedCrossRefGoogle Scholar
  8. Bottura, C., and Cotinho, V., 1965, The effect of pyrimethamine on the human chromosomes, Rev. Brasil. Biol., 25:145–147.PubMedGoogle Scholar
  9. Breitman, T. R., Maury, P. B., and Toal, J. N., 1972, Loss of deoxyribonucleic acid-thymine during thymine starvation of Escherichia coli, J. Bacteriol., 112:646–648.PubMedGoogle Scholar
  10. Brendel, M., and Lagjahr, U. G., 1974, “Thymineless death” in a strain of Saccharomyces cerevisiae auxotrophic for deoxy-thymidine-5′-monophosphate, Molec. Gen. Genet., 131:351–358.PubMedCrossRefGoogle Scholar
  11. Brookwell, R., Daniel, A., Turner, G., and Fishburn, J., 1982, The fragile X(q27) form of X-linked mental retardation: FUdr as an inducing agent for fra(X)(q27) expression in lymphocytes, fibroblasts and amniocytes, Am. J. Med. Genet., 13:139–148.PubMedCrossRefGoogle Scholar
  12. Cairns, J., 1981, The origin of human cancers, Nature (London), 294:313–318.CrossRefGoogle Scholar
  13. Cassiman, J. J., de Clerq, E., and van den Berghe, H., 1983, Induction of sister chromatid exchange by 5-substituted 2′-deoxyuridines, Mutat. Res., 117:317–327.PubMedCrossRefGoogle Scholar
  14. Cohen, S. S., and Earner, H. D., 1954, Studies on unbalanced growth in Escherichia coli, Proc. Natl. Acad. Sci. USA, 40:885–893.PubMedCrossRefGoogle Scholar
  15. Cohen, S. S., and Barner, H. D., 1956, Studies on the induction of thymine deficiency and on the effects of thymine and thymine analogs in Escherichia coli, J. Bacteriol., 71:588–597.PubMedGoogle Scholar
  16. Cohen, S. S., Flaks, J. G., Barner, H. D., Loeb, M. R., and Lichtenstein, J., 1958, The mode of action of 5-fluorouracil and its derivatives, Proc. Natl. Acad. Sci. USA, 44:1004–1012.PubMedCrossRefGoogle Scholar
  17. Dalla-Favera, R., Bregni, M., Erikson, J., Patterson, D., Gallo, R. C., Croce, C. M., 1982, Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells, Proc. Natl. Acad. Sci. USA, 79:7824–7827.PubMedCrossRefGoogle Scholar
  18. Dalla-Favera, R., Martinotti, S., Gallo, R. C., Erikson, J., and Croce, C. M., 1983, Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas, Science, 219:963–967.PubMedCrossRefGoogle Scholar
  19. Das, S. K., Benditt, E. P., and Loeb, L. A., 1983, Rapid changes in deoxynucleoside triphosphate pools in mammalian cells treated with mutagens, Biochem. Biophys. Res. Commun., 114:458–464.PubMedCrossRefGoogle Scholar
  20. Drake, J. W., and Greening, E. O., 1970, Suppression of chemical mutagenesis in bacteriophage T4 by genetically modified DNA polymerases, Proc. Natl. Acad. Sci. USA, 66:823–829.PubMedCrossRefGoogle Scholar
  21. Dustin, P., 1950, Sur lés lesions nucléaires et chromosomiques provoquées chez la souris par les acides diamino-pteroyl-glutamiques et par la diaminopurine, Rev. d’Hematol., 5:603–617.Google Scholar
  22. Eckardt, F., Kunz, B. A., and Haynes, R. H., 1983, Variation in mutation and recombination frequencies over a range of thymidylate concentrations in a diploid thymidylate auxotroph of yeast, Current Genet., 7:399–402.CrossRefGoogle Scholar
  23. Fogel, M., 1972, Induction of virus synthesis in polyoma-transformed cells by DNA antimetabolites and by irradiation after pre-treatment with 5-bromodeoxyuridine, Virol., 49:12–22.CrossRefGoogle Scholar
  24. Freifelder, D., 1969, Single strand breaks in bacterial DNA associated with thymine starvation, J. Molec. Biol., 45:1–7.PubMedCrossRefGoogle Scholar
  25. Gallant, J., and Spottswood, T., 1964, Measurement of the stability of the repressor of alkaline phosphatase synthesis in Escherichia coli, Proc. Natl. Acad. Sci. USA, 52:1591–1598.PubMedCrossRefGoogle Scholar
  26. Galloway, S. M., 1977, Ataxia telangiectasia: the effects of chemical mutagens and x-rays on sister chromatid exchanges in blood lymphocytes, Mutat. Res., 45:343–349.PubMedCrossRefGoogle Scholar
  27. Game, J. C., Johnston, L. H., and von Borstel, R. C., 1979, Enhanced mitotic recombination in a ligase deficient mutant of the yeast Saccharomyces cerevisiae, Proc. Natl. Acad. Sci. USA, 76:4589–4592.PubMedCrossRefGoogle Scholar
  28. Glover, T. W., 1981, FUdR induction of the X chromosome fragile site: evidence for the mechanism of folic acid and thymidine inhibition, Am. J. Hum. Genet., 33:234–242.PubMedGoogle Scholar
  29. Hansmann, I., 1974, Chromosome aberrations in metaphase II oocytes. Stage sensitivity in the mouse oogenesis to amethopterin and cyclophosphamide, Mutat. Res., 22:175–191.PubMedCrossRefGoogle Scholar
  30. Haynes, R. H., and Kunz, B. A., 1981, DNA repair and mutagenesis in yeast, in: “The Molecular Biology of the Yeast Saccharomyces: Life Cycle and Inheritance,” J. N. Strathern, E. W. Jones, and J. R. Broach, eds., Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, pp. 371–414.Google Scholar
  31. Hsu, T. C., Humphrey, R. M., and Somers, C. E., 1964, Responses of Chinese hamster and L cells to 2′-deoxy-5-fluoro-uridine and thymidine, J. Natl. Cancer Inst., 32:839–855.Google Scholar
  32. Jensen, M. K., 1967, Chromosome studies in patients treated with azathioprine and amethopterin, Acta Medica Scandanavica, 182:445–455.CrossRefGoogle Scholar
  33. Jensen, M. K., and Nyfors, A., 1979, Cytogenetic effect of methotrexate on human cells in vivo. Comparison between results obtained by chromosome studies on bone-marrow cells and blood lymphocytes and by the micronucleus test, Mutat. Res., 64:339–343.PubMedGoogle Scholar
  34. Jones, P. A., Benedict, W. F., Baker, M. S., Mondai, S., Rapp, U., and Heidelberger, C., 1976, Oncogenic transformation of C3H/10T½ clone 8 mouse embryo cells by halogenated pyrimidine nucleosides, Cancer Res., 36:101–107.PubMedGoogle Scholar
  35. Kaung, D. T., and Swartzendruber, A. A., 1969, Effect of chemotherapeutic agents on chromosomes of patients with lung cancer, Dis. Chest, 55:98–100.PubMedCrossRefGoogle Scholar
  36. Kinsella, A., and Radman, M., 1978, Tumor promoter induces sister chromatid exchanges: relevance to mechanisms of carcinogenesis, Proc. Natl. Acad. Sci. USA, 75:6149–6153.PubMedCrossRefGoogle Scholar
  37. Korn, D., and Weissbach, A., 1962, Thymineless induction in Eschericia coli K12 (λ), Biochim. Biophys. Acta, 61:885–896.Google Scholar
  38. Kozinski, A. W., and Kozinski, P. B., 1964, Replicative fragmentation in T4 bacteriophage DNA II. Biparental molecular recombination, Proc. Natl. Acad. Sci. USA, 52:211–218.PubMedCrossRefGoogle Scholar
  39. Kunz, B. A., 1982, Genetic effects of deoxyribonucleotide pool imbalances, Environ. Mutagen., 4:695–725.PubMedCrossRefGoogle Scholar
  40. Kunz, B. A., Barclay, B. J., Game, J. C., Little, J. G., and Haynes, R. H., 1980a, Induction of mitotic recombination in yeast by starvation for thymine nucleotides, Proc. Natl. Acad. Sci. USA, 77:6057–6061.PubMedCrossRefGoogle Scholar
  41. Kunz, B. A., Barclay, B. J., and Haynes, R. H., 1980b, A simple, rapid plate assay for mitotic recombination, Mutat. Res., 73:215–220.PubMedCrossRefGoogle Scholar
  42. Kunz, B. A., and Haynes, R. H., 1982, DNA repair and the genetic effects of thymidylate stress in yeast, Mutat. Res., 93:353–375.CrossRefGoogle Scholar
  43. Kunz, B. A., Taylor, G. R., Konforti, B., Glickman, B. W., and Haynes, R. H., 1984, Inhibition of thymidylate biosynthesis induces mitotic unequal sister chromatid recombination in Saccharomyces cerevisiae, Current Genet., 8:211–217.CrossRefGoogle Scholar
  44. Little, J. W., 1976, The effect of bromouracil on recombination in phage lambda, Virol., 72:530–535.CrossRefGoogle Scholar
  45. Little, J. G., and Haynes, R. H., 1979, Isolation and characterization of yeast mutants auxotrophic for 2′-deoxythymidine 5′-monophosphate, Molec. Gen. Genet., 168:141–151.PubMedCrossRefGoogle Scholar
  46. Lozzio, C. B., 1968, Thymineless death and chromosome aberrations induced by fluorodeoxyuridine in G1 cells, Genetics, 60:199.Google Scholar
  47. Luchnik, K. V., Fesenko, E. V., and Ouchinnikova, V. G., 1976, Critical periods of the mitotic cycle: Influence of aminopterin and thymidine on production of chromosomal aberrations in Crepis capillaris, Mutat. Res., 34:367–388.PubMedCrossRefGoogle Scholar
  48. Maier, P., and Schmid, W., 1976, Ten model mutagens evaluated by the micronucleus test, Mutat. Res., 40:325–338.PubMedCrossRefGoogle Scholar
  49. Marcu, K. B., Harris, L. J., Stanton, L. W., Erikson, J., Watt, R., and Croce, C. M., 1983, Transcriptionally active c-myc onco-gene is contained within NIARD, a DNA sequence associated with chromosome translocations in B cell neoplasia, Proc. Natl. Acad. Sci. USA, 80:519–523.PubMedCrossRefGoogle Scholar
  50. McBurney, M. W., and Whitmore, G. F., 1974, Isolation and characterization of folate deficient mutants of Chinese hamster cells, Cell, 2:173–182.PubMedCrossRefGoogle Scholar
  51. McFall, M., and Magasanik, B., 1962, The effect of thymine deprivation on protein synthesis in Escherichia coli, Biochim. Biophys. Acta, 55:920–928.CrossRefGoogle Scholar
  52. Melnyk, J., Duffy, D. M., and Sparkes, R. S., 1971, Human mitotic and meiotic chromosome damage following in vivo exposure to methotrexate, Clin. Genet., 11:28–31.Google Scholar
  53. Murcia, C. R., and Rombela, J. J. A., 1972, Cytological aberrations produced by methotrexate in mouse ascites tumors, Mutat. Res., 14:405–412.CrossRefGoogle Scholar
  54. Ockey, C. H., Jsu, T. C., and Richardson, L. C., 1968, Chromosome damage induced by 5-fluoro-2′-deoxyuridine in relation to the cell cycle of the Chinese hamster, J. Natl. Cancer Inst., 40:465–478.Google Scholar
  55. Pall, M. L., 1981, Gene-amplification model of carcinogenesis, Proc. Natl. Acad. Sci. USA, 78:2465–2468.PubMedCrossRefGoogle Scholar
  56. Perry, P. E., 1983, Induction of sister chromatid exchanges (SCEs) by thymidine and the potentiation of mutagen-induced SCEs in Chinese hamster cells, Mutat. Res., 109:219–229.PubMedCrossRefGoogle Scholar
  57. Potter, C. G., 1971, Induction of polyploidy by concentrated thymidine, Exp. Cell Res., 68:442–448.PubMedCrossRefGoogle Scholar
  58. Putrament, A., 1967, On the mechanism of mitotic recombination in Aspergillus nidulans. I. Intragenic recombination and DNA replication, Molec. Gen. Genet., 100:307–320.PubMedCrossRefGoogle Scholar
  59. Rueckert, R. R., and Mueller, G. C., 1960, Studies on unbalanced growth in tissue culture. I. Induction and consequences of thymine deficiency, Cancer Res., 20:1584–1591.PubMedGoogle Scholar
  60. Ryan, T. J., Boddington, M. M., and Spriggs, A. I., 1965, Chromosomal abnormalities produced by folic acid antagonists, Br. J. Dermatol., 77:541–555.PubMedCrossRefGoogle Scholar
  61. Sedwick, W. D., Kutler, M., and Brown, O. E., 1981, Antifolate-induced misincorporation of deoxyuridine monophosphate into DNA: Inhibition of high molecular weight DNA synthesis in human lymphoblastoid cells, Proc. Natl. Acad. Sci. USA, 78:917–921.PubMedCrossRefGoogle Scholar
  62. Sheng-Ong, G. L. C., Keath, E. J., Piccoli, S. P., and Cole, M. D., 1982, Novel myc oncogene RNA from abortive immunoglobulin gene recombination in mouse plasmacytomas, Cell, 31:443–452.CrossRefGoogle Scholar
  63. Sutherland, G. R., 1979, Heritable fragile sites on human chromosomes I. Factors affecting expression in lymphocyte culture, Am. J. Hum. Genet., 31:125–135.PubMedGoogle Scholar
  64. Taub, R., Kirsch, I., Morton, C., Lenoir, G., Swan, D., Tronik, S., Aaronson, S., and Leder, P., 1982, Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells, Proc. Natl. Acad. Sci. USA, 79:7837–7841.PubMedCrossRefGoogle Scholar
  65. Voorhees, J. J., Janzen, M. K., Harrell, E. R., and Chakrabarti, S. G., 1969, Cytogenetic evaluation of methotrexate-treated psoriatic patients, Arch. Dermatol., 100:269–274.PubMedCrossRefGoogle Scholar
  66. Yang, S-J., Hahn, G. M., and Bagshaw, M. A., 1966, Chromosome aberrations induced by thymidine, Exp. Cell Res., 42:130–135.PubMedCrossRefGoogle Scholar
  67. Yoshinaga, K., 1973, Double strand scission of DNA involved in thymineless death of Escherichia coli 15 Tau, Biochim. Biophys. Acta, 294:204–213.Google Scholar
  68. Yunis, J. J., 1983, The chromosomal basis of human neoplasia, Science, 221:227–236.PubMedCrossRefGoogle Scholar
  69. Zimmermann, F. K., Schwaier, R., and von Laer, U., 1966, Mitotic recombination induced in Saccharomyces cerevisiae with nitrous acid, diethylsulfate and carcinogenic alkylating nitrosamides, Z. Verebungsl., 98:230–246.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • Robert H. Haynes
    • 1
  • Bernard A. Kunz
    • 1
  1. 1.Department of BiologyYork UniversityTorontoCanada

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