2001 Fiscal Year Annual Research Report

フリーラジカルによる細胞傷害に対する防御機構の研究

Research Project

Project/Area Number	11694290
Research Institution	KYUSHU UNIVERSITY
Principal Investigator	中別府雄作九州大学, 生体防御医学研究所, 教授 (30180350)
Co-Investigator(Kenkyū-buntansha)	冨永洋平九州大学, 生体防御医学研究所, 助手 (90304823) 作見邦彦九州大学, 生体防御医学研究所, 助手 (50211933) 古市正人九州大学, 生体防御医学研究所, 助手 (70199420) 續輝久九州大学, 大学院・医学研究院, 教授 (40155429)
Keywords	活性酸素 / 8-オキソグアニン / 2-ハイドロキシアデニン / 基質認識 / 発がん / 自然突然変異 / 肺腫瘍 / 遺伝子欠損マウス
Research Abstract	酸素呼吸に依存して生命を維持している好気性生物では,酸素呼吸や酸化還元反応で必然的に生じる活性酸素などのフリーラジカルによる細胞傷害は不可避である.本研究では,このような細胞障害に対する生体防御に関わる遺伝子とその遺伝子産物について,その機能と構造を分子レベルで明らかにし,さらに細胞・個体レベルでの生理機能を解明することを目的として,九州大学・續博士,フランス国立科学研究センター・Takahashi博士,同・Boiteux博士,米国国立がん研究所・Kasprzak博士,米国ジョンスホプキンス大学・Ichikawa博士の研究グループとの共同研究を進めて,以下の成果を挙げた. (1)MTH1蛋白質の基質認識機構の解析 MutTとMTH1に高度に保存された「phosphohydrolase module」とMTH1蛋白質にのみ存在する「C末端領域」は,ともにMTH1のみが認識する2-OH-dATPとMutTとMTH1の両者が認識する8-oxo-dGTPの識別には関与しないことを明らかにした.「C末端領域」は,基質識別には関与しないもののMTH1の構造を安定に維持するうえで必須である.MTH1蛋白質による2-OH-dATPと8-oxo-dGTPの認識には,W117とD119残基が必須であり,それぞれのアミノ酸残基が2つのヌクレオチドの認識に異なる役割を担うことを明らかにした. (2)OGG1,MTH1遺伝子欠損マウスにおける自然発がんの解析野生型,OGG1遺伝子欠損,MTH1遺伝子欠損,およびMTH1,OGG1二重遺伝子欠損マウスを作製し,それぞれのマウスの自然発癌頻度(67〜82週)を比較したところ,OGG1遺伝子欠損マウスで肺腫瘍が高頻度(約50%)に発生することが観察された。また,遺伝的背景によって結果が異なることからmodifier geneの存在が示唆された。

Research Products

(14 results)

All Other

All Publications (14 results)

[Publications] Iida, T., Nakabeppu, Y.他4名: "Accumulation of 8-oxo-2'-deoxyguanosine and increased expression of hMTH1 protein in brain tumors"Neuro-Oncology. 3・2. 73-81 (2001)
[Publications] Tsuchimoto, D., Nakabeppu, Y.他5名: "Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen"Nucleic Acids Research. 29・11. 2349-2360 (2001)
[Publications] Jaiswal, M., Nakabeppu, Y.他3名: "Human oggl, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide"Cancer Research. 61・17. 6388-6393 (2001)
[Publications] Tsuzuki, T., Nakatsuru, Y.他13名: "Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase"Proceedings of National Academy of Sciences of USA. 98. 11456-11461 (2001)
[Publications] Furuta, A., Iida, T., Nakabeppu, Y., Iwaki, T.: "Expression of hMTH1 in the hippocampi of control and Alzheimer's disease"Neuroreport. 12・13. 2895-2899 (2001)
[Publications] Kasprzak, KS., Nakabeppu, Y.他7名: "Intracellular distribution of the antimutagenic enzyme MTH1 in the liver, kidney, and testis of F344 rats, and its modulation by cadmium"Experimental Toxicology and Pathology. 53. 325-336 (2001)
[Publications] Nakabeppu, Y.: "Molecular Genetics and Structural Biology of Human MutT Homolog, MTH1"Mutation Research. 477・1-2. 59-70 (2001)
[Publications] Nakabeppu, Y: "Regulation of Intracellular Localization of Human MTH1, OGG1 and MYH Proteins for Repair of Oxidative DNA Damage"Progress in Nucleic Acid Research and Molecular Biolology. 68. 75-94 (2001)
[Publications] Nakabeppu, Y., Tominaga, Y.他6名: "Mechanisms Protecting Genomic Integrity from Damage Caused by Reactive Oxygen Species : Implications for Carcinogenesis and Neurodegeneration"Environmental Mutagen Research. 23. 197-209 (2002)
[Publications] Iida, T., Furuta, A., Nishioka, K., Nakabeppu, Y., Iwaki, T.: "Expression of mitochondrial OGG1-2a protein for 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer's disease brain"Acta Neuropathologica. 103. 20-25 (2002)
[Publications] Hayashi, H., Nakabeppu, Y.他4名: "Replication-associated repair of adenine : 8-oxoguanine mispairs by MYH"Current Biology. 12. 1-20 (2002)
[Publications] Fujikawa, K., Nakabeppu, Y.他5名: "8-Chloro-dGTP, a hypochlorous acid-modified nucleotide, is hydrolyzed by hMTH1, the human MutT homolog"FEBS Letter. 512. 149-151 (2002)
[Publications] Kikuchi, H., Nakabeppu, Y.他4名: "Impairment of mitochondrial DNA repair enzymes against accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis"Acta Neuropathologica. (印刷中).
[Publications] Sakai, Y., Nakabeppu, Y.他5名: "A Molecular Basis for the Selective Recognition of 2-Hydroxy-dATP and 8-Oxo-dGTP by MTH1 Which Is Known to Suppress Spontaneous Carcinogenesis"Journal of Biological Chemistry. (印刷中).

2001 Fiscal Year Annual Research Report

フリーラジカルによる細胞傷害に対する防御機構の研究

Principal Investigator

中別府 雄作 九州大学, 生体防御医学研究所, 教授 (30180350)

Research Products

[Publications] Iida, T., Nakabeppu, Y.他4名: "Accumulation of 8-oxo-2'-deoxyguanosine and increased expression of hMTH1 protein in brain tumors"Neuro-Oncology. 3・2. 73-81 (2001)

[Publications] Tsuchimoto, D., Nakabeppu, Y.他5名: "Human APE2 protein is mostly localized in the nuclei and to some extent in the mitochondria, while nuclear APE2 is partly associated with proliferating cell nuclear antigen"Nucleic Acids Research. 29・11. 2349-2360 (2001)

[Publications] Jaiswal, M., Nakabeppu, Y.他3名: "Human oggl, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide"Cancer Research. 61・17. 6388-6393 (2001)

[Publications] Tsuzuki, T., Nakatsuru, Y.他13名: "Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase"Proceedings of National Academy of Sciences of USA. 98. 11456-11461 (2001)

[Publications] Furuta, A., Iida, T., Nakabeppu, Y., Iwaki, T.: "Expression of hMTH1 in the hippocampi of control and Alzheimer's disease"Neuroreport. 12・13. 2895-2899 (2001)

[Publications] Kasprzak, KS., Nakabeppu, Y.他7名: "Intracellular distribution of the antimutagenic enzyme MTH1 in the liver, kidney, and testis of F344 rats, and its modulation by cadmium"Experimental Toxicology and Pathology. 53. 325-336 (2001)

[Publications] Nakabeppu, Y.: "Molecular Genetics and Structural Biology of Human MutT Homolog, MTH1"Mutation Research. 477・1-2. 59-70 (2001)

[Publications] Nakabeppu, Y: "Regulation of Intracellular Localization of Human MTH1, OGG1 and MYH Proteins for Repair of Oxidative DNA Damage"Progress in Nucleic Acid Research and Molecular Biolology. 68. 75-94 (2001)

[Publications] Nakabeppu, Y., Tominaga, Y.他6名: "Mechanisms Protecting Genomic Integrity from Damage Caused by Reactive Oxygen Species : Implications for Carcinogenesis and Neurodegeneration"Environmental Mutagen Research. 23. 197-209 (2002)

[Publications] Iida, T., Furuta, A., Nishioka, K., Nakabeppu, Y., Iwaki, T.: "Expression of mitochondrial OGG1-2a protein for 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer's disease brain"Acta Neuropathologica. 103. 20-25 (2002)

[Publications] Hayashi, H., Nakabeppu, Y.他4名: "Replication-associated repair of adenine : 8-oxoguanine mispairs by MYH"Current Biology. 12. 1-20 (2002)

[Publications] Fujikawa, K., Nakabeppu, Y.他5名: "8-Chloro-dGTP, a hypochlorous acid-modified nucleotide, is hydrolyzed by hMTH1, the human MutT homolog"FEBS Letter. 512. 149-151 (2002)

[Publications] Kikuchi, H., Nakabeppu, Y.他4名: "Impairment of mitochondrial DNA repair enzymes against accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis"Acta Neuropathologica. (印刷中).

[Publications] Sakai, Y., Nakabeppu, Y.他5名: "A Molecular Basis for the Selective Recognition of 2-Hydroxy-dATP and 8-Oxo-dGTP by MTH1 Which Is Known to Suppress Spontaneous Carcinogenesis"Journal of Biological Chemistry. (印刷中).

中別府雄作九州大学, 生体防御医学研究所, 教授 (30180350)