Molecular pathological analysis of defects in DNA base excision repair system using gene modified mice

• Project/Area Number: 16390119
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kyushu University
• Principal Investigator: TSUCHIMOTO Daisuke Kyushu University, Med.Inst.Bioreg., Research Associate, 生体防御医学研究所, 助手 (70363348)
• Co-Investigator(Kenkyū-buntansha): NAKABEPPU Yusaku Kyushu University, Med.Inst.Bioreg., Professor, 生体防御医学研究所, 教授 (30180350)
• Project Period (FY): 2004 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥12,900,000 (Direct Cost: ¥12,900,000); Fiscal Year 2006: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2005: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2004: ¥6,500,000 (Direct Cost: ¥6,500,000)
• Keywords: oxidative stress / 8-oxoguanine / neurodegeneration / Parkinson's disease / Huntington's disease / mitochondrial genome / nuclear genome / cell death / 酸化DNA損傷 / 塩基除去修復 / 遺伝子改変マウス / 損傷ヌクレオチド分解酵素

Research Abstract

Using gene modified mice, we have revealed the followings,
(A) Accumulations of nucleic acids with oxidized bases in genomic DNA or nucleotide pool in nucleus, cytoplasm or mitochondria cause cell death through at least two different pathways.
(B) Defects in repair enzymes for DNA with damaged bases including basic sites or defects in cleaning enzymes for nucleotides with damaged bases cause mutagenesis, cell cycle arrest or cell death at cell level, which result in dysfunction of brain neuron, dyshematopoiesis, growth retardation, cardiodysfunction, or increase of tumorigenesis in mouse individuals.
Using human peripheral lymphocytes, we have revealed the following,
(C) Typical oxidized purine, 8-oxo-guanine (8-oxoG) is unevenly distributed in the normal human genome and the distribution pattern is conserved among different individuals. Moreover, 8-oxoG might be one of the main causes of frequent recombinations and SNPs in human genome.

Research Products

• [Journal Article] MUTYH-null mice are susceptible to spontaneous and oxidative-stress-induced intestinal tumorigenesis. (2007)
  • Author(s): Sakamoto, K. et al.
  • Journal Title: Cancer Res. (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] RNA Polymerase II bypasses 8-oxoguanine in the presence of transcription elongation factor TFIIS. (2007)
  • Author(s): Kuraoka, I., et al.
  • Journal Title: DNA Repair 6 Pages: 841-851
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Accumulation of 8-oxo-deoxyguanosine in Cardiovascular Tissues with the Development of Hypertension. (2007)
  • Author(s): Ohtsubo, T. et al.
  • Journal Title: DNA Repair 6 Pages: 760-769
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Significance of error-avoiding mechanisms for oxidative DNA damage in carcinogenesis. (2007)
  • Author(s): Tsuzuki, T. et al.
  • Journal Title: Cancer Sci 98(4) Pages: 465-470
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Oxidative Damage in Nucleic Acids and Parkinson's Disease. (2007)
  • Author(s): Nakabeppu, Y. et al.
  • Journal Title: J. Neurosci. Res. 85(5) Pages: 919-934
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prevention of the mutagenecity and cytotoxicity of oxidized purine nucleotides, in Oxidative Damage to Nucleic Acids. (2007)
  • Author(s): Nakabeppu, Y. et al.
  • Journal Title: Georgetown, TX. : Landes Bioscience/Eurekah (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] RNA Polymerase II bypasses 8-oxoguanine in the presence of transcription elongation factor TFIIS. (2007)
  • Author(s): Kuraoka, I. et al.
  • Journal Title: DNA Repair 6 Pages: 841-851
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Oxidative Damage in Nucleic Acids and Parkinson's Disease. (2007)
  • Author(s): Nakabeppu, Y. et al.
  • Journal Title: J.Neurosci.Res. 85(5) Pages: 919-934
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] RNA Polymerase II bypasses 8-oxoguanine in the presence of transcription elongation factor TFIIS. (2007)
  • Author(s): Kuraoka, I., Suzuki, K., Ito, S., Hayashida, M., Seah, J., Kwei, M., Ikegami, T., Handa, H., Nakabeppu, Y., Tanaka,K
  • Journal Title: DNA Repair (印刷中)
• [Journal Article] Accumulation of 8-oxo-deoxyguanosine in Cardiovascular Tissues with the Development of Hypertension. (2007)
  • Author(s): Ohtsubo, T., Ohya, Y., Nakamura, Y., Kansui, Y., Furuichi, M., Matsumura, K., Fujii, K., Iida, M., Nakabeppu,Y.
  • Journal Title: DNA Repair (印刷中)
• [Journal Article] Significance of error-avoiding mechanisms for oxidative DNA damage in carcinogenesis. (2007)
  • Author(s): Tsuzuki, T., Nakatsu, Y., Nakabeppu, Y.
  • Journal Title: Cancer Sci (印刷中)
• [Journal Article] Oxidative Damage in Nucleic Acids and Parkinson's Disease. (2007)
  • Author(s): Nakabeppu, Y., Tsuchimoto, D., Yamaguchi, H., Sakumi, K.
  • Journal Title: J.Neurosci.Res. 85・5 Pages: 919-934
  • NAID: 120000985083
• [Journal Article] Recognition of Nucleotide Analogs Containing the 7,8-Dihydro-8-oxo Structure by the Human MTH1 Protein. (2006)
  • Author(s): Kamiya, H. et al.
  • Journal Title: J. Biochem. 140(6) Pages: 843-849
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Crystallization and preliminary X-ray analysis of human MTH1 complexed with two oxidized nucleotides, 8-oxo-dGMP and 2-oxo-dATP. (2006)
  • Author(s): Nakamura, T. et al.
  • Journal Title: Acta Crystallograph. Sect. F. Struct. Biol. Cryst. Commun. 62(12) Pages: 1283-1285
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-henyl-1,2,3,6-tetrahydropyridine (2006)
  • Author(s): Yamaguchi H. et al.
  • Journal Title: Cell Death and Differ. 13(4) Pages: 551-563
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome. (2006)
  • Author(s): Ohno, M. et al.
  • Journal Title: Genome Res. 16(5) Pages: 567-575
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis. (2006)
  • Author(s): Akatsuka, S. et al.
  • Journal Title: Am. J. Pathol. 169(4) Pages: 1328-1342
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson's disease. (2006)
  • Author(s): Arai, T. et al.
  • Journal Title: Acta Neuropathol. 112(2) Pages: 139-145
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal. (2006)
  • Author(s): Sakai, Y. et al.
  • Journal Title: J. Mol. Med. 84(8) Pages: 660-670
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides. (2006)
  • Author(s): Nakabeppu, Y. et al.
  • Journal Title: DNA Repair 5(7) Pages: 761-772
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced exitotoxicity (2006)
  • Author(s): Kajitani K. et al.
  • Journal Title: J. Neurosci. 26(6) Pages: 1688-1698
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids. (2006)
  • Author(s): Nakabeppu, Y. et al.
  • Journal Title: Biol. Chem. 387(4) Pages: 373-379
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids. (2006)
  • Author(s): Nakabeppu, Y. et al.
  • Journal Title: Biol.Chem. 387(4) Pages: 373-379
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Recognition of Nucleotide Analogs Containing the 7,8-Dihydro-8-oxo Structure by the Human MTH1 Protein. (2006)
  • Author(s): Kamiya, H. et al.
  • Journal Title: J.Biochem. 140(6) Pages: 843-849
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Crystallization and preliminary X-ray analysis of human MTH1 complexed with two oxidized nucleotides, 8-oxo-dGMP and 2-oxo-dATP. (2006)
  • Author(s): Nakamura, T. et al.
  • Journal Title: Acta Crystallograph.Sect.F.Struct.Biol.Cryst.Commun. 62(12) Pages: 1283-1285
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-pheny1-1,2,3,6-tetrahydropyridine (2006)
  • Author(s): Yamaguchi H. et al.
  • Journal Title: Cell Death and Differ. 13(4) Pages: 551-63
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis (2006)
  • Author(s): Akatsuka, S. et al.
  • Journal Title: Am.J.Pathol. 169(4) Pages: 1328-1342
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal. (2006)
  • Author(s): Sakai, Y. et al.
  • Journal Title: J.Mol.Med. 84(8) Pages: 660-670
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced exitotoxicity (2006)
  • Author(s): Kajitani K. et al.
  • Journal Title: J.Neurosci. 26(6) Pages: 1688-1698
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids. (2006)
  • Author(s): Nakabeppu, Y., Sakumi, K., Sakamoto, K., Tsuchimoto, D., Tsuzuki, T., Nakatsu,Y.
  • Journal Title: Biol.Chem. 387・4 Pages: 373-379
• [Journal Article] Recognition of Nucleotide Analogs Containing the 7,8-Dihydro-8-oxo Structure by the Human MTH1 Protein. (2006)
  • Author(s): Kamiya, H., Cadena-Amaro, C., Dugue, L., Yakushiji, H., Minakawa, N., Matsuda, A., Pochet, S., Nakabeppu, Y., Harashima,H.
  • Journal Title: J.Biochem. 140・6 Pages: 843-849
• [Journal Article] Crystallization and preliminary X-ray analysis of human MTH1 complexed with two oxidized nucleotides, 8-oxo-dGMP and 2-oxo-dATP. (2006)
  • Author(s): Nakamura, T., Kitaguchi, Y., Miyazawa, M., Kamiya, H., Toma, S., Ikemizu, S., Shirakawa, M., Nakabeppu, Y, Yamagata, Y.
  • Journal Title: Acta Crystallograph.Sect.F.Struct.Biol.Cryst.Commun. 62・12 Pages: 1283-1285
• [Journal Article] 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. (2006)
  • Author(s): Yamaguchi, H., Kajitani, K., Dan, Y., Furuichi, M., Ohno, M., Sakumi, K., Kang, D., Nakabeppu,Y.
  • Journal Title: Cell Death Differ. 13・4 Pages: 551-563
• [Journal Article] A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome. (2006)
  • Author(s): Ohno, M., Miura, T., Furuichi, M., Tominaga, Y., Tsuchimoto, D., Sakumi, K., Nakabeppu,Y.
  • Journal Title: Genome Res. 16・5 Pages: 567-575
• [Journal Article] Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis. (2006)
  • Author(s): Akatsuka, S., Aung, T.T., Dutta, K.K., Jiang, L, Lee, W.H., Liu, Y.T., Onuki, J., Shirase, T., Yamasaki, K., Ochi, H., Naito, Y., Yoshikawa, T., Kasai, H., Tominaga, Y., Sakumi, K., Nakabeppu, Y., Kawai, Y., Uchida, K., Yamasaki, A., Tsuruyama, T., Yamada,Y., Toyokuni,S.
  • Journal Title: Am.J.Pathol. 169・4 Pages: 1328-1342
• [Journal Article] Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson's disease. (2006)
  • Author(s): Arai, T., Fukae, J., Hatano, T., Kubo, S., Ohtsubo, T., Nakabeppu, Y., Mori, H., Mizuno, Y, Hattori,N.
  • Journal Title: Acta Neuropathol. 112・2 Pages: 139-145
• [Journal Article] The GT to GC single nucleotide polymorphism at the beginning of an altemative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal. (2006)
  • Author(s): Sakai, Y., Oda, H., Yoshimura, D., Furuichi, M., Kang, D., Iwai, S., Hara, T., Nakabeppu,Y.
  • Journal Title: J.Mol.Med. 84・8 Pages: 660-670
• [Journal Article] MTH1,an oxidized purine nucleoside triphosphatase,prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides. (2006)
  • Author(s): Nakabeppu, Y., Kajitani, K., Sakamoto, K., Yamaguchi, H., Tsuchimoto,D.
  • Journal Title: DNA Repair 5・7 Pages: 761-772
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced exitotoxicity (2006)
  • Author(s): Kousuke Kajitani et al.
  • Journal Title: The Journal of Neuroscience 26(6) Pages: 1688-1698
• [Journal Article] Characterization of the structure and expression of mouse Itpa gene and its related sequences in the mouse genome (2005)
  • Author(s): Behmanesh M. et al.
  • Journal Title: DNA Research 12 Pages: 39-51
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA (2005)
  • Author(s): Ushijima Y. et al.
  • Journal Title: Nucleic Acids Res. 33(2) Pages: 672-682
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hematopoietic Tissue-Specific Expression of Mouse Neil3 for Endonuclease VIII-Like Protein (2005)
  • Author(s): Torisu K. et al.
  • Journal Title: J. Biochem. 138(6) Pages: 763-772
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hematopoietic Tissue-Specific Expression of Mouse Neil3 for Endonuclease VIII-Like Protein (2005)
  • Author(s): Torisu K. et al.
  • Journal Title: J.Biochem. 138(6) Pages: 763-772
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hematopoietic Tissue-Specific Expression of Mouse Neil3 for Endonuclease VIII-Like Protein (2005)
  • Author(s): Kumiko Torisu et al.
  • Journal Title: The Journal of Biochemistry 138(6) Pages: 763-772
• [Journal Article] 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 (2005)
  • Author(s): Hiroo Yamaguchi et al.
  • Journal Title: Cell Death and Differentiation Nov.,4
• [Journal Article] A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA (2005)
  • Author(s): Yasuhiro Ushijima et al.
  • Journal Title: Nucleic Acids Research 33(2) Pages: 672-682
• [Journal Article] Characterization of the structure and expression of mouse Itpa gene and its related sequences in the mouse genome (2005)
  • Author(s): Mehrdad Behmanesh et al.
  • Journal Title: DNA research (In press)
• [Journal Article] MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain (2004)
  • Author(s): Tominaga Y. et al.
  • Journal Title: Nucleic Acids Res. 32(10) Pages: 3198-3211
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice (2004)
  • Author(s): Ide Y.et al.
  • Journal Title: Blood 104(13) Pages: 4097-4103
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] MUTYH prevents OGG1 or APEX1 from inappropriately processing its substrate or reaction product with its C-terminal domain (2004)
  • Author(s): Yohei Tominaga et al.
  • Journal Title: Nucleic Acids Research 32(10) Pages: 3198-3211
• [Journal Article] Growth retardation and dyslymphopoiesis accompanied by G2/M arrest in APEX2-null mice (2004)
  • Author(s): Yasuhito Ide et al.
  • Journal Title: Blood 104(13) Pages: 4097-4103
• [Book] Prevention of the mutagenecity and cytotoxicity of oxidized purine nucleotides, in Oxidative Damage to Nucleic Acids. (2007)
  • Author(s): Nakabeppu, Y. et al.
  • Publisher: Georgetown, TX. : Landes Bioscience / Eurekah (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Prevention of the mutagenecity and cytotoxicity of oxidized purine nuckeotides,In Oxidative Damage to Nucleic Acids. (2007)
  • Author(s): Nakabeppu, Y., Behmanesh, M., Yamaguchi, H., Yoshimura, D., Sakumi, K.
  • Total Pages: 14
  • Publisher: Georgetown,TX. : Landes Bioscience/Eurekah