The Role of Micronutrients in DNA Synthesis and Maintenance

  • Robert A. Jacob
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 472)


Recent research has indicated that the micronutrients, folate, niacin, and vitamin C may be important for various aspects of DNA and chromosome integrity. Folate is an essential cofactor for biosynthesis of deoxynucleotides and DNA methylation reactions. Niacin provides ADP-ribose units for proteins which are involved in DNA replication and repair. Vitamin C, a primary intracellular antioxidant, may provide protection against oxidative DNA base damage. Evidence for the importance of these micronutrients in DNA synthesis and repair is reviewed. The evidence is substantial for some of these nutrients and merely suggestive, even controversial, for others.


Folate Deficiency Folate Depletion Thymine Glycol Uracil Misincorporation Lymphocyte Micronucleus 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Selhub, J. and Rosenberg, LH., 1996, Folic acid. In: Present Knowledge in Nutrition, 7th Edition ( Ziegler, E.E. and Filer Jr., L.J., eds.), pp. 206–219. International Life Sciences Institute Press, Washington, D.C.Google Scholar
  2. 2.
    James, S.J., Cross, D.R., and Miller, B.J.,1992, Alterations in nucleotide pools in rats fed diets deficient in choline, methionine, and/or folic acid. Carcinogenesis 13: 2471–474.Google Scholar
  3. 3.
    James, S.J., Basnakian, A.G., and Miller, B.J.,1994, In vitro folate deficiency induces deoxynucleotide pool imbalance, apoptosis, and mutagenesis in Chinese Hamster ovary cells. Cancer Res. 54:5075–5080.Google Scholar
  4. 4.
    James, S.J., Miller, B.J., Cross, D.R., Mcgarrity, L.J., and Morris, S.M., 1993, The essentiality of folate for the maintenance of deoxynucleotide precursor pools, DNA synthesis, and cell cycle progression in PHA-stimulated lymphocytes. Environ. Health Perspectives 101: 173–178.Google Scholar
  5. 5.
    James, S.J., Miller, B.J., McGarrity, L.J., and Morris, S.M., 1994, The effect of folic acid and/or methionine deficiency on deoxyribonucleotide pools and cell cycle distribution in mitogen-stimulated rat lymphocytes. Cell Proliferation 27: 395–406.CrossRefGoogle Scholar
  6. 6.
    Pogribny, I.P., Muskhelishvili, L., Miller, B.J., and James, S.J., 1997, Presence and consequence of uracil in preneoplastic DNA from folate/methyl-deficient rats. Carcinogenesis 18: 2071–2076.PubMedCrossRefGoogle Scholar
  7. 7.
    Pogribny, I.P., Basnakian, A.G., Miller, B.J., Lopatina, N.G., Poirier, L.A., and James, S.J., 1995, DNA strand breaks in genomic DNA and within the p53 gene are associated with hypomethylation in livers of folate/methyl deficient rats. Cancer Research 55: 1894–1901.PubMedGoogle Scholar
  8. 8.
    Balaghi, M. and Wagner, C., 1993, DNA methylation in folate deficiency—use of CpG methylase. Biochem. Biophys. Res. Commun. 193: 1184–1190.PubMedCrossRefGoogle Scholar
  9. 9.
    Kim, Y-I., Pogribny, I.P., Basnakian, A.G., Miller, J.W., Selhub, J., James, S.J., and Mason, J.B., 1997, Folate deficiency in rats induces DNA strand breaks and hypomethylation within the p53 tumor suppressor gene. Am. J. Clin. Nutr. 65: 46–52.PubMedGoogle Scholar
  10. 10.
    Jacob, R.A., Gretz, D.M., Taylor, P.C., James, S.J., Pogribny, I.P., Miller, B.J., Henning, S.M., and Swendseid, M.E., 1998, Moderate folate depletion increases plasma homocysteine and decreases lymphocyte DNA methylation in postmenopausal women. J. Nutr. 128: 1204–1212.PubMedGoogle Scholar
  11. 11.
    Blount, B.C., Mack, M.M., Wehr, C.M., MacGregor, J.T., Hiatt, R.A., Wang, G., Wickramasinghe, S.N., Everson, R.B., and Ames, B.N., 1997, Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proc. Natl. Acad. Sci. USA 94: 3290–3295.PubMedCrossRefGoogle Scholar
  12. 12.
    MacGregor, J.T., Wehr, C.M., Hiatt, R.A., Peters, B., Tucker, J.D., Langlois, R.G., Jacob, R.A., Jensen, R.H., Yager, J.W., Shigenaga, M.K., Frei, B., Eynon, B.P., and Ames, B.N., 1997, Spontaneous genetic damage in man: Evaluation of interindividual variability, relationship among markers of damage, and influence of nutritional status. Mutation Research 377: 125–135.PubMedCrossRefGoogle Scholar
  13. 13.
    Titenko-Holland, N., Jacob, R.A., Shang, N., Balaraman, A., and Smith, M.T., 1998, Micronuclei in lymphocytes and exfoliated buccal cells of postmenopausal women with dietary changes in folate. Mutation Res. 417: 101–114.PubMedCrossRefGoogle Scholar
  14. 14.
    Kim, Y.-I. and Christman, J.K., 1995, Moderate folate deficiency does not cause global hypomethylation of hepatic and colonic DNA or c-myc-specific hypomethylation of colonic DNA in rats. Am. J. Clin. Nutr. 61: 1083–1090.PubMedGoogle Scholar
  15. 15.
    Everson, R.B., Wehr, C.M., Erexson, G.L., and MacGregor, J.T., 1988, Association of marginal folate depletion with increased human chromosomal damage in vivo: demonstration by analysis of micronucleated erythrocytes. J. Natl. Cancer Inst. 80: 525–529.PubMedCrossRefGoogle Scholar
  16. 16.
    Fenech, M.F. and Rinaldi, J.R., 1994, The relationship between micronuclei in human lymphocytes and plasma level of vitamin C, vitamin E, vitamin B-12, and folic acid. Carcinogenesis 15: 1405–1411.PubMedCrossRefGoogle Scholar
  17. 17.
    Fenech, M.F., Dreosti, I.E., and Rinaldi, J.R., 1997, Folate, vitamin B12, homocysteine status and chromosome damage rate in lymphocytes of older men. Carcinogenesis 18: 1329–1336.PubMedCrossRefGoogle Scholar
  18. 18.
    Food and Nutrition Board, Institute of Medicine. 1998, Folate. In: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academy Press, Washington, D.C.Google Scholar
  19. 19.
    Merlo, A., Herman, J.G., Mao, L., Lee, D.J., Gabrielson, E., Burger, P.C., Baylin, S.B., and Sidransky, D., 1995, Cpg island methylation is associated with transcriptional silencing of the tumour suppresor p16/CDKN2/MTS1 in human cancers. Nature Medicine 1: 686–692.PubMedCrossRefGoogle Scholar
  20. 20.
    James, S.J., Miller, B.J., Basnakian, A.G., Pogribny, I.P., Pogribna, M., and Muskhelishvili, L., 1997, Apoptosis and proliferation under conditions of deoxynucleotide pool imbalance in liver of folate/methyl deficient rats. Carcinogenesis 18: 287–293PubMedCrossRefGoogle Scholar
  21. 21.
    Fenech, M., Aitken, C., and Rinaldi, J., 1998, Folate, vitamin B12, homocysteine status and DNA damage in young Australian adults. Carcinogenesis 19: 1163–1171.PubMedCrossRefGoogle Scholar
  22. 22.
    Butterworth, Jr., C.E., Hatch, K.D., Macaluso, M., Cole, P., Sauberlich, H.E., Soong, S.-J., Borst, M., and Baker, V.V., 1992, Folate deficiency and cervical dysplasia. J. Am. Med. Assoc. 267: 528–533.CrossRefGoogle Scholar
  23. 23.
    Glynn, S.A. and Albanes, D., 1994, Folate and cancer: a review of the literature. Nutr. Cancer 22: 101–119.PubMedCrossRefGoogle Scholar
  24. 24.
    Mason, J.B., 1994, Folate and colonic carcinogenesis: searching for a mechanistic understanding. J. Nutr. Biochem. 5: 170–175.CrossRefGoogle Scholar
  25. 25.
    Lucock, M.D., Wild, J., Schorah, C.J., Levene, M.I., and Hartley, R., 1994, The methylfolate axis in neural tube defects: in vitro characterization and clinical investigation. Biochem. Med. Met. Biol. 52: 101–114.CrossRefGoogle Scholar
  26. 26.
    Fang, J.Y., Xiao, S.D., Zhu, S.S., Yuan, J.M., Qiu, D.K., and Jiang, S.1,1997, Relationship of plasma folic acid and status of DNA methylation in human gastric cancer. J Gastroenterol. 32: 171–175.Google Scholar
  27. 27.
    Lautier, D., Lagueux, J., Thibodeau, L., Menard, S., and Poirier, G.G., 1993, Molecular and biochemical features of poly(ADP-ribose) metabolism. Mol. Cell. Biochem. 122: 171–193.PubMedCrossRefGoogle Scholar
  28. 28.
    Stierum, R.H.,Vanherwijnen, M.H.M., Hageman G.J., and Kleinjans, J.C.S., 1994, Increased poly(ADPribose) polymerase activity during repair of (+/-)-anti-benzo[a]pyrene diolepoxide-induced DNA damage in human peripheral blood lymphocytes in vitro. Carcinogenesis 15: 745–751.CrossRefGoogle Scholar
  29. 29.
    Zhang, J.Z., Henning, S.M., and Swendseid, M.E., 1993, Poly(ADP-ribose) polymerase activity and DNA strand breaks are affected in tissues of niacin-deficient rats. J. Nutr. 123: 1349–1355.PubMedGoogle Scholar
  30. 30.
    James, S.J. and Yin, L., 1989, Diet-induced DNA damage and altered nucleotide metabolism in lymphocytes from methyl-donor-deficient rats. Carcinogenesis 10: 1209–1214.PubMedCrossRefGoogle Scholar
  31. 31.
    Henning, S.M., Swendseid, M.E., and Coulson, W.F., 1997, Male rats fed methyl-and folate-deficient diets with or without niacin develop hepatic carcinomas associated with decreased tissue NAD concentrations and altered poly(ADP-ribose) polymerase activity. J. Nutr. 127: 30–36.PubMedGoogle Scholar
  32. 32.
    Buettner, G.R., 1993, The pecking order of free radicals and antioxidants: lipid peroxidation, alphatocopherol, and ascorbate. Archives Biochem. Biophys. 300: 535–543.Google Scholar
  33. 33.
    Bendich, A., Machlin, L.J., Scandurra, O., Burton, G.W., and Wayner, D.M., 1986, The antioxidant role of vitamin C, Adv. Free Rad. Biol. Med. 2: 419–444.CrossRefGoogle Scholar
  34. 34.
    Sies, H., Stahl, W., and Sundquist, A.R., 1992, Antioxidant functions of vitamins. Annals NY Acad Sci 669: 7–20.CrossRefGoogle Scholar
  35. 35.
    Frei, B., England, L., and Ames, B.N., 1989, Ascorbate is an outstanding antioxidant in human blood plasma, Proc. Natl. Acad. Sci. USA 86: 6377–6381.Google Scholar
  36. 36.
    Winkler, B.S., 1992, Unequivocal evidence in support of the nonenzymatic redox coupling between glutathione/glutathione disulfide and ascorbic acid/dehydroascorbic acid, Biochim. Biophys. Acta 1117: 287–290.Google Scholar
  37. 37.
    Martensson, J., Han, J., Griffith, O.W., and Meister, A., 1993, Glutathione ester delays the onset of scurvy in ascorbate-deficient guinea pigs. Proc. Natl. Acad. Sci. USA 90: 317–321.PubMedCrossRefGoogle Scholar
  38. 38.
    Jacob, R.A., 1995, The integrated antioxidant system. Nutr. Research 15: 755–766.CrossRefGoogle Scholar
  39. 39.
    Fraga, C.G., Motchnik, RA., Shigenaga, M.K., Helbock, H.J., Jacob, R.A., and Ames, B.N., 1991, Ascorbic acid protects against endogenous oxidative DNA damage in human sperm. Proc. Natl. Acad. Sci. USA 88: 11003–11006.PubMedCrossRefGoogle Scholar
  40. 40.
    Anderson, D., Phillips, B.J., Yu, T., Edwards, A.J., Ayesh, R., and Butterworth, K.R., 1997, The effects of vitamin C supplementation on biomarkers of oxygen radical generated damage in human volunteers with low or high cholesterol levels. Environ. Mol. Mutagen 30: 161–174.PubMedCrossRefGoogle Scholar
  41. 41.
    Podmore, I.D., Griffiths, H.R., Herbert, K.E., Mistry, N., Mistry, P., and Lunec, J., 1998, Vitamin C exhibits pro-oxidant properties. Nature 392: 559.PubMedCrossRefGoogle Scholar
  42. 42.
    Rehman, A., Collis, C.S., Yang, M., Kelly, M., Diplock, A.T., Halliwell, B., and Rice-Evans, C., 1998, The effects of iron and vitamin C co-supplementation on oxidative damage to DNA in healthy volunteers. Biochem. Biophys. Res. Commun. 246: 293–298.Google Scholar
  43. 43.
    Witt, E.H., Reznick, Z., Viguie, C.A., Starke-Reed, P., and Packer, L., 1992, Exercise, oxidative damage and effects of antioxidant manipulation. Am. Inst. Nutr. 122: 766–773.Google Scholar
  44. 44.
    Loft, S., Vistisen, K., Ewertz, M., Tjonneland, A., Overvad, K., and Poulsen, H.E., 1992, Oxidative DNA damage estimated by 8-hydroxydeoxyguanosine excretion in humans: influence of smoking, gender and body mass index. Carcinogenesis 13: 2241–2247.PubMedCrossRefGoogle Scholar
  45. 45.
    Prieme, H., Loft, S., Nyyssonen, K., Salonen, J.T., and Poulsen, H.E., 1997, No effect of supplementation with vitamin E, ascorbic acid, or coenzyme Q10 on oxidative DNA damage estimated by 8oxo-7,8-dihydro-2’-deoxyguanosine excretion in smokers. Am. J. Clin. Nutr. 65: 503–507.PubMedGoogle Scholar
  46. 46.
    Green, M.H.L., Lowe, J.E., Waugh, A.EW, Aldridge, K.E., Cole, J., and Arlett, C.E,1994, Effect of diet and vitamin C on DNA strand breakage in freshly-isolated human white blood cells. Mutation Res. 316: 91–102.Google Scholar
  47. 47.
    Pohl, H. and Reidy, J.A., 1989, Vitamin C intake influences the bleomycin-induced chromosome damage assay: implications for detection of cancer susceptibility and chromosome breakage syndromes, Mutation Res. 224: 247–252.PubMedCrossRefGoogle Scholar
  48. 48.
    Block G., 1991, Vitamin C and cancer prevention: the epidemiologic evidence. Am. J. Clin. Nutr. 53: 270S - 282S.PubMedGoogle Scholar
  49. 49.
    Fontham, E.T.H., 1994. Vitamin C, vitamin C-rich foods and cancer: Epidemiologic studies. In: Frei B., ed. Natural antioxidants in health and disease. San Diego: Academic Press 157–197.Google Scholar
  50. 50.
    Leaf, C.D., Vecchio, A.J., Roe, D.A., and Hotchkiss, J.H., 1987, Influence of ascorbic acid dose on Nnitrosoproline formation in humans. Carcinogenesis 8: 791–795.PubMedCrossRefGoogle Scholar
  51. 51.
    Dyke, G.W., Craven, J.L., Hall, R., and Garner, R.C., 1994, Effect of vitamin C supplementation on gastric mucosal DNA damage. Carcinogenesis 15: 291–295.PubMedCrossRefGoogle Scholar
  52. 52.
    Dyke, G.W., Craven, J.L., Hall, R., and Garner, R.C., 1994, Effect of vitamin C upon gastric mucosal O-6-alkyltransferase activity and on gastric vitamin C levels. Cancer Letters 86: 159–165.PubMedCrossRefGoogle Scholar
  53. 53.
    Young, J.C., Kenyon, E.M., and Calabrese, E.J., 1990, Inhibition of beta-glucuronidase in human urine by ascorbic acid. Human and Experimental Toxicology 9: 165–170.PubMedCrossRefGoogle Scholar
  54. 54.
    Busey, H.J.R., DeCosse, J.J., Deschiner, E.E., Eyers, A.A., Lesser, M.L., Morson, B.C., Ritchie, S.M., Thomson, J.P.S., Wadsworth, J., 1982, A randomized trial of ascorbic acid in polyposis coli. Cancer (Philadelphia) 50: 1434–1439.CrossRefGoogle Scholar
  55. 55.
    McKeown-Eyssen, G., Holloway, C., Jazmaji, V., Bright-See, E., Dion, R, and Bruce, W.R., 1988, A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps. Cancer Res. 48: 4701–4705.Google Scholar
  56. 56.
    Cahill, R.J., Osullivan, K.R., Mathias, R.M., Beattie, S., Hamilton, H., and Omorain, C., 1993, Effects of vitamin antioxidant supplementation on cell kinetics of patients with adenomatous polyps. Clin. Med. 34: 963–967.Google Scholar
  57. 57.
    Hofstad, B., Almendingen, K., Vatn, M., Andersen, S.N., Owen, R.W., Larsen, S., and Osnes, M., 1998, Growth and recurrence of colorectal polyps: A double-blind 3-year intervention with calcium and antioxidants. Digestion 59: 148–156.PubMedCrossRefGoogle Scholar
  58. 58.
    Blot, W.J., Li, J.Y., Taylor, P.R., Guo, W, Dawsey, S., Wang, G.Q., Yang, C.S., Zheng, S.E, Gail, M., Li, G.Y., Yu, Y., Liu, B.Q.,Tangrea, J., Sun, Y.H., Liu, E, Fraumeni Jr., J.F., Zhang, Y.H., and Li, B.,1993, Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J. Nat. Cancer Inst. 85: 1483–1492.Google Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Robert A. Jacob
    • 1
  1. 1.Western Human Nutrition Research Center U.S. Department of Agriculture Agricultural Research ServiceUniversity of CaliforniaDavisUSA

Personalised recommendations