Prevention of the Mutagenicity and Cytotoxicity of Oxidized Purine Nucleotides

  • Yusaku Nakabeppu
  • Mehrdad Behmanesh
  • Hiroo Yamaguchi
  • Daisuke Yoshimura
  • Kunihiko Sakumi
Part of the Molecular Biology Intelligence Unit book series (MBIU)


Damage to nucleic acids is particularly hazardous because the genetic information in genomic DNA, such as nuclear and mitochondrial DNA, can be altered. Damage accumulated in cellular DNAs often initiates programmed cell death, as well as mutagenesis. The former may cause degenerative diseases, and the latter may result in neoplasia and hereditary diseases. The accumulation of oxidative damage in cellular DNA or RNA is a result of the incorporation of oxidized nucleotides generated in nucleotide pools, as well as a result of their direct oxidation. Recent progress in studies of the sanitization of nucleotide pools, in addition to DNA repair, have revealed the significance of the oxidation of free nucleotides to be unexpectedly large, in comparison to the direct oxidation of DNA.


Amyotrophic Lateral Sclerosis Tyrosine Hydroxylase Ribonucleotide Reductase Direct Oxidation Nucleotide Pool 
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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  1. 1.
    Ames BN, Gold LS. Endogenous mutagens and the causes of aging and cancer. Mutat Res 1991; 250:3–16.PubMedGoogle Scholar
  2. 2.
    Nakabeppu Y, Tsuchimoto D, Furuichi M et al. The defense mechanisms in mammalian cells against oxidative damage in nucleic acids and their involvement in the suppression of mutagenesis and cell death. Free Radic Res 2004; 38:423–429.PubMedCrossRefGoogle Scholar
  3. 3.
    Nakabeppu Y, Tsuchimoto D, Ichinoe A et al. Biological significance of the defense mechanisms against oxidative damage in nucleic acids caused by reactive oxygen species: From mitochondria to nuclei. Ann NY Acad Sci 2004; 1011:101–111.PubMedCrossRefGoogle Scholar
  4. 4.
    Kasai H, Nishimura S. Hydroxylation of deoxyguanosine at the C-8 position by ascorbic acid and other reducing agents. Nucleic Acids Res 1984; 12:2137–2145.PubMedCrossRefGoogle Scholar
  5. 5.
    Mo JY, Maki H, Sekiguchi M. Hydrolytic elimination of a mutagenic nucleotide, 8-oxodGTP, by human 18-kilodalton protein: Sanitization of nucleotide pool. Proc Natl Acad Sci USA 1992; 89:11021–11025.PubMedCrossRefGoogle Scholar
  6. 6.
    Kamiya H, Kasai H. Formation of 2-hydroxydeoxyadenosine triphosphate, an oxidatively damaged nucleotide, and its incorporation by DNA polymerases. Steady-state kinetics of the incorporation. J Biol Chem 1995; 270:19446–19450.PubMedCrossRefGoogle Scholar
  7. 7.
    Fujikawa K, Kamiya H, Yakushiji H et al. The oxidized forms of dATP are substrates for the human MutT homologue, the hMTH1 protein. J Biol Chem 1999; 274:18201–18205.PubMedCrossRefGoogle Scholar
  8. 8.
    Tassotto ML, Mathews CK. Assessing the metabolic function of the MutT 8-oxodeoxyguanosine triphosphatase in Escherichia coli by nucleotide pool analysis. J Biol Chem 2002; 277:15807–15812.PubMedCrossRefGoogle Scholar
  9. 9.
    Brischwein K, Engelcke M, Riedinger HJ et al. Role of ribonucleotide reductase and deoxynucleotide pools in the oxygen-dependent control of DNA replication in Ehrlich ascites cells. Eur J Biochem 1997; 244:286–293.PubMedCrossRefGoogle Scholar
  10. 10.
    Koc A, Wheeler LJ, Mathews CK et al. Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools. J Biol Chem 2004; 279:223–230.PubMedCrossRefGoogle Scholar
  11. 11.
    Maki H, Sekiguchi M. MutT protein specifically hydrolyses a potent mutagenic substrate for DNA synthesis. Nature 1992; 355:273–275.PubMedCrossRefGoogle Scholar
  12. 12.
    Fujikawa K, Kamiya H, Kasai H. The mutations induced by oxidatively damaged nucleotides, 5-formyl-dUTP and 5-hydroxy-dCTP, in Escherichia coli. Nucleic Acids Res 1998; 26:4582–4587.PubMedCrossRefGoogle Scholar
  13. 13.
    Kamiya H, Kasai H. 2-Hydroxy-dATP is incorporated opposite G by Escherichia coli DNA polymerase III resulting in high mutagenicity. Nucleic Acids Res 2000; 28:1640–1646.PubMedCrossRefGoogle Scholar
  14. 14.
    Satou K, Harashima H, Kamiya H. Mutagenic effects of 2-hydroxy-dATP on replication in a HeLa extract: Induction of substitution and deletion mutations. Nucleic Acids Res 2003; 31:2570–2575.PubMedCrossRefGoogle Scholar
  15. 15.
    Inoue M, Kamiya H, Fujikawa K et al. Induction of chromosomal gene mutations in Escherichia coli by direct incorporation of oxidatively damaged nucleotides. New evaluation method for mutagenesis by damaged DNA precursors in vivo. J Biol Chem 1998; 273:11069–11074.PubMedCrossRefGoogle Scholar
  16. 16.
    Tajiri T, Maki H, Sekiguchi M. Functional cooperation of MutT, MutM and MutY proteins in preventing mutations caused by spontaneous oxidation of guanine nucleotide in Escherichia coli. Mutat Res 1995; 336:257–267.PubMedGoogle Scholar
  17. 17.
    Taddei F, Hayakawa H, Bouton M et al. Counteraction by MutT protein of transcriptional errors caused by oxidative damage. Science 1997; 278:128–130.PubMedCrossRefGoogle Scholar
  18. 18.
    Kobayashi M, Ohara-Nemoto Y, Kaneko M et al. Potential of Escherichia coli GTP cyclohydrolase II for hydrolyzing 8-oxo-dGTP, a mutagenic substrate for DNA synthesis. J Biol Chem 1998; 273:26394–26399.PubMedCrossRefGoogle Scholar
  19. 19.
    Kamiya H, Murata-Kamiya N, Iida E et al. Hydrolysis of oxidized nucleotides by the Escherichia coli Orf135 protein. Biochem Biophys Res Commun 2001; 288:499–502.PubMedCrossRefGoogle Scholar
  20. 20.
    Hori M, Fujikawa K, Kasai H et al. Dual hydrolysis of diphosphate and triphosphate derivatives of oxidized deoxyadenosine by Orf17 (NtpA), a MutT-type enzyme. DNA Repair 2005; 4:33–39.PubMedCrossRefGoogle Scholar
  21. 21.
    Kamiya H, Iida E, Murata-Kamiya N et al. Suppression of spontaneous and hydrogen peroxide-induced mutations by a MutT-type nucleotide pool sanitization enzyme, the Escherichia coli Orf135 protein. Genes Cells 2003; 8:941–950.PubMedCrossRefGoogle Scholar
  22. 22.
    Shimokawa H, Fujii Y, Furuichi M et al. Functional significance of conserved residues in the phosphohydrolase module of Escherichia coli MutT protein. Nucleic Acids Res 2000; 28:3240–3249.PubMedCrossRefGoogle Scholar
  23. 23.
    Massiah MA, Saraswat V, Azurmendi HF et al. Solution structure and NH exchange studies of the MutT pyrophosphohydrolase complexed with Mg2+ and 8-oxo-dGMP, a tightly bound product. Biochemistry 2003; 42:10140–10154.PubMedCrossRefGoogle Scholar
  24. 24.
    Mildvan AS, Xia Z, Azurmendi HF et al. Structures and mechanisms of Nudix hydrolases. Arch Biochem Biophys 2005; 433:129–143.PubMedCrossRefGoogle Scholar
  25. 25.
    Sakumi K, Furuichi M, Tsuzuki T et al. Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis. J Biol Chem 1993; 268:23524–23530.PubMedGoogle Scholar
  26. 26.
    Furuichi M, Yoshida MC, Oda H et al. Genomic structure and chromosome location of the human mutT homologue gene MTH1 encoding 8-oxo-dGTPase for prevention of A:T to C:G transversion. Genomics 1994; 24:485–490.PubMedCrossRefGoogle Scholar
  27. 27.
    Fujikawa K, Kamiya H, Yakushiji H et al. Human MTH1 protein hydrolyzes the oxidized ribonucleotide, 2-hydroxy-ATP. Nucleic Acids Res 2001; 29:449–454.PubMedCrossRefGoogle Scholar
  28. 28.
    Mishima M, Sakai Y, Itoh N et al. Structure of human MTH1, a Nudix family hydrolase that selectively degrades oxidized purine nucleoside triphosphates. J Biol Chem 2004; 279:33806–33815.PubMedCrossRefGoogle Scholar
  29. 29.
    Yakushiji H, Maraboeuf F, Takahashi M et al. Biochemical and physicochemical characterization of normal and variant forms of human MTH1 protein with antimutagenic activity. Mutat Res 1997; 384:181–194.PubMedGoogle Scholar
  30. 30.
    Fujii Y, Shimokawa H, Sekiguchi M et al. Functional significance of the conserved residues for the 23-residue module among MTH1 and MutT family proteins. J Biol Chem 1999; 274:38251–38259.PubMedCrossRefGoogle Scholar
  31. 31.
    Sakai Y, Furuichi M, Takahashi M et al. A molecular basis for the selective recognition of 2-hydroxy-dATP and 8-oxo-dGTP by human MTH1. J Biol Chem 2002; 277:8579–8587.PubMedCrossRefGoogle Scholar
  32. 32.
    Cai JP, Ishibashi T, Takagi Y et al. Mouse MTH2 protein which prevents mutations caused by 8-oxoguanine nucleotides. Biochem Biophys Res Commun 2003; 305:1073–1077.PubMedCrossRefGoogle Scholar
  33. 33.
    Ishibashi T, Hayakawa H, Sekiguchi M. A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides. EMBO Rep 2003; 4:479–483.PubMedCrossRefGoogle Scholar
  34. 34.
    Ito R, Hayakawa H, Sekiguchi M et al. Multiple enzyme activities of Escherichia coli MurT protein for sanitization of DNA and RNA precursor pools. Biochemistry 2005; 44:6670–6674.PubMedCrossRefGoogle Scholar
  35. 35.
    Ishibashi T, Hayakawa H, Ito R et al. Mammalian enzymes for preventing transcriptional errors caused by oxidative damage. Nucleic Acids Res 2005; 33:3779–3784.PubMedCrossRefGoogle Scholar
  36. 36.
    Hayakawa H, Hofer A, Thelander L et al. Metabolic fate of oxidized guanine ribonucleotides in mammalian cells. Biochemistry 1999; 38:3610–3614.PubMedCrossRefGoogle Scholar
  37. 37.
    Ehrenberg A. Free radical transfer, fluctuating structure and reaction cycle of ribonucleotide reductase. Biosystems 2001; 62:9–12.PubMedCrossRefGoogle Scholar
  38. 38.
    Ogawa T, Ueda Y, Yoshimura K et al. Comprehensive analysis of cytosolic Nudix hydrolases in Arabidopsis thaliana. J Biol Chem 2005; 280: 25277–25283.PubMedCrossRefGoogle Scholar
  39. 39.
    Nunoshiba T, Ishida R, Sasaki M et al. A novel Nudix hydrolase for oxidized purine nucleoside triphosphates encoded by ORFYLR151c (PCD1 gene) in Saccharomyces cerevisiae. Nucleic Acids Res 2004; 32:5339–5348.PubMedCrossRefGoogle Scholar
  40. 40.
    Tsuzuki T, Egashira A, Igarashi H et al. Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase. Proc Natl Acad Sci USA 2001; 98:11456–11461.PubMedCrossRefGoogle Scholar
  41. 41.
    Russo M, Blasi M, Chiera F et al. The oxidized deoxynucleoside triphosphate pool is a significant contributor to genetic instability in mismatch repair-deficient cells. Mol Cell Biol 2004; 24:465–474.PubMedCrossRefGoogle Scholar
  42. 42.
    Sakumi K, Tominaga Y, Furuichi M et al. Ogg1 Knockout-associated lung tumorigenesis and its suppression by Mth1 gene disruption. Cancer Res 2003; 63:902–905.PubMedGoogle Scholar
  43. 43.
    Yoshimura D, Sakumi K, Ohno M et al. An oxidized purine nucleoside triphosphatase, MTH1, suppresses cell death caused by oxidative stress. J Biol Chem 2003; 278:37965–37973.PubMedCrossRefGoogle Scholar
  44. 44.
    Okamoto K, Toyokuni S, Kim WJ et al. Overexpression of human mutT homologue gene messenger RNA in renal-cell carcinoma: Evidence of persistent oxidative stress in cancer. Int J Cancer 1996; 65:437–441.PubMedCrossRefGoogle Scholar
  45. 45.
    Iida T, Furuta A, Kawashima M et al. Accumulation of 8-oxo-2′-deoxyguanosine and increased expression of hMTH1 protein in brain tumors. Neuro-oncol 2001; 3:73–81.PubMedCrossRefGoogle Scholar
  46. 46.
    Kennedy CH, Pass HI, Mitchell JB. Expression of human MutT homologue (hMTH1) protein in primary nonsmall-cell lung carcinomas and histologically normal surrouding tissue. Free Radic Biol Med 2003; 34:1447–1457.PubMedCrossRefGoogle Scholar
  47. 47.
    Jungst C, Cheng B, Gehrke R et al. Oxidative damage is increased in human liver tissue adjacent to hepatocellular carcinoma. Hepatology 2004; 39:1663–1672.PubMedCrossRefGoogle Scholar
  48. 48.
    Speina E, Arczewska KD, Gackowski D et al. Contribution of hMTH1 to the maintenance of 8-oxoguanine levels in lung DNA of nonsmall-cell lung cancer patients. J Natl Cancer Inst 2005; 97:384–395.PubMedCrossRefGoogle Scholar
  49. 49.
    Jaiswal M, LaRusso NF, Nishioka K et al. Human Ogg1, a protein involvel in the repair of 8-oxoguanine, is inhibited by nitric oxide. Cancer Res 2001; 61:6388–6393.PubMedGoogle Scholar
  50. 50.
    Shimura-Miura H, Hattori N, Kang D et al. Increased 8-oxo-dGTPase in the mitochondria of substantia nigral neurons in Parkinson’s disease. Ann Neurol 1999; 46: 920–924.PubMedCrossRefGoogle Scholar
  51. 51.
    Zhang J, Perry G, Smith MA et al. Parkinson’s disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol 1999; 154:1423–1429.PubMedGoogle Scholar
  52. 52.
    Nunomura A, Perry G, Aliev G et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001; 60:759–767.PubMedGoogle Scholar
  53. 53.
    Kikuchi H, Furuta A, Nishioka Ki K et al. Impairment of mitochondrial DNA repair enzymes against accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis. Acta Neuropathol 2002; 103:408–414.PubMedCrossRefGoogle Scholar
  54. 54.
    Nishioka K, Ohtsubo T, Oda H et al. Expression and differential intracellular localization of two major forms of human 8-oxoguanine DNA glycosylase encoded by alternatively spliced OGG1 mRNAs. Mol Biol Cell 1999; 10:1637–1652.PubMedGoogle Scholar
  55. 55.
    Fukae J, Takanashi M, Kubo SI et al. Expression of 8-oxoguanine DNA glycosylase (OGG1) in Parkinson’s disease and related neurodegenerative disorders. Acta Neuropathol 2005; 109:256–262.PubMedCrossRefGoogle Scholar
  56. 56.
    Furuta A, Iida T, Nakabeppu Y et al. Expression of hMTH1 in the hippocampi of control and Alzheimer’s disease. Neuroreport 2001; 12: 2895–2899.PubMedCrossRefGoogle Scholar
  57. 57.
    Iida T, Furuta A, Nishioka K et al. Expression of 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer’s disease brain. Acta Neuropathol 2002; 103:20–25.PubMedCrossRefGoogle Scholar
  58. 58.
    Yamaguchi H, Kajitani K, Dan Y et al. MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Cell Death Differ Advance online publication 2005, (doi: 10.1038/sj.cdd.4401788).Google Scholar
  59. 59.
    Spencer JP, Whiteman M, Jenner A et al. Nitrite-induced deamination and hypochlorite-induced oxidation of DNA in intact human respiratory tract epithelial cells. Free Radic Biol Med 2000; 28:1039–1050.PubMedCrossRefGoogle Scholar
  60. 60.
    Chung JH, Back JH, Park YI et al. Biochemical characterization of a novel hypoxanthine/xanthine dNTP pyrophosphatase from Methanococcus jannaschii. Nucleic Acids Res 2001; 29: 3099–3107.PubMedCrossRefGoogle Scholar
  61. 61.
    Lin S, McLennan AG, Ying K et al. Cloning expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the Itpa gene. J Biol Chem 2001; 276: 18695–18701.PubMedCrossRefGoogle Scholar
  62. 62.
    Chung JH, Park HY, Lee JH et al. Identification of the dITP-and XTP-hydrolyzing protein from Escherichia coli. J Biochem Mol Biol 2002; 35:403–408.PubMedGoogle Scholar
  63. 63.
    Clyman J, Cunningham RP. Escherichia coli K-12 mutants in which viability is dependent on recA function. J Bacteriol 1987; 169:4203–4210.PubMedGoogle Scholar
  64. 64.
    Bradshaw JS, Kuzminov A. RdgB acts to avoid chromosome fragmentation in Escherichia coli. Mol Microbiol 2003; 48:1711–1725.PubMedCrossRefGoogle Scholar
  65. 65.
    Vanderheiden BS. Inosine triphosphate in human erythrocytes: A genetic treat. Stockholm: Proc Xth Congress Int Soc Blood Transf, 1964:540–548.Google Scholar
  66. 66.
    Sumi S, Marinaki AM, Arenas M et al. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet 2002; 111: 360–367.PubMedCrossRefGoogle Scholar
  67. 67.
    Behmanesh M, Sakumi K, Tsuchimoto D et al. Characterization of the structure and expression of mouse Itpa gene and its related sequences in the mouse genome. DNA Res 2005; 12:39–51.PubMedCrossRefGoogle Scholar
  68. 68.
    Burney S, Tamir S, Gal A et al. A mechanistic analysis of nitric oxide-induced cellular toxicity. Nitric Oxide 1997; 1:130–144.PubMedCrossRefGoogle Scholar
  69. 69.
    Nakabeppu Y. MTH1, an oxidized purine nucleoside triphosphatase suppresses mitochondrial dysfunction and cell death caused by oxidative stress. Protein Nucleic Acid and Enzyme 2005; 50:940–948.Google Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Yusaku Nakabeppu
    • 1
  • Mehrdad Behmanesh
    • 2
  • Hiroo Yamaguchi
    • 1
  • Daisuke Yoshimura
    • 1
  • Kunihiko Sakumi
    • 1
  1. 1.Division of Neurofunctional Genomics, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
  2. 2.Department of Genetics School of SciencesTarbiat Modarres UniversityTehranIran

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