1998 Fiscal Year Annual Research Report

突然変異の分子病態

Research Project

Project/Area Number	08280104
Research Institution	Nara Institute of Science and Technology
Principal Investigator	真木寿治奈良先端科学技術大学院大学, バイオサイエンス研究科, 教授 (20199649)
Co-Investigator(Kenkyū-buntansha)	林健志九州大学, 遺伝情報実験施設, 教授 (00019671) 能美健彦国立医薬品食品衛生研究所, 変異遺伝部, 室長(研究職) (30150890) 中村健司東京大学, 医科学研究所, 助手 (90253533) 続輝久九州大学, 医学部, 教授 (40155429) 葛西宏産業医科大学, 産業生体科学研究所, 教授 (40152615)
Keywords	DNA複製 / 複製エラー / ミスマッチ修復 / 酸素ラジカル / DNA修復 / フレームシフト / 繰り返し配列 / ノックアウトマウス
Research Abstract	本研究計画での主要な問題点は自然突然変異の発生原因や変異を抑制する機構の解明と生体でのそれらの制御や生物学的あるいは医学的影響を明らかにすることである。本年度は以下の2つの項目について研究を実施し、新たな知見を得た。 1. 自然突然変異の分子機構:新しい改良型標的遺伝子を用いた解析から、大腸菌でのDNA複製エラーに起因する塩基置換変異の部位特異性を明らかにし、さらに校正機能およびミスマッチ修復機構による変異抑制機能の効率や特異性を検討した。また、繰り返し配列に依存して高頻度に発生するスリッペ-ジェラーの分子機構の新しいモデルを提出した。DNAの自然損傷については、酸素ラジカルによる変異原性ヌクレオチドおよびDNA損傷について、体系的にそれらの変異誘発能を詳細に検討した。 2. 高等生物における突然変異の特異性:酸素ラジカルによる損傷を修復する酵素をコードする遺伝子としてOGGl遺伝子に焦点を絞り、ノックアウトマウスの作成に成功した。このマウスでの突然変異率と発がんの発生頻度の検討を開始した。ヒト発癌でのミスマッチ修復欠損が引き起こす癌抑制遺伝子の変異パターンについて詳細な検討を行った。染色体上のマイクロサテライトDNAの繰り返し数の変化がそれらの末端で引き起こされることを見出した。歯状核赤核淡蒼球ルイ体萎縮症の原因遺伝子のリピート数の変化のパターンについても検討した。

Research Products
(17 results)

All Other

All Publications (17 results)

[Publications] H.Kasai: "DNA modifications by the mutagen glyoxal : adduction to G and C, deamination of C and GC and GA cross-linking" Carcinogenesis. 19. 1459-1465 (1998)
[Publications] M.Inoue: "Induction of chromosomal gene mutations in Escherichia coli by direct incorporation of oxidatively damaged nucleotides." J.Biol.Chem.273. 11069-11074 (1998)
[Publications] N.Murata-Kamiya: "Nucleotide excision repair proteins may be involved in the fixation of glyoxal-induced mutagenesis in Escherichia coli." Biochem.Biophys.Res.Commun.248. 412-417 (1998)
[Publications] T.Tsuzuki: "Embryonic stem cell gene targeting using bacteriophage λ vectors generated by phage-plasmid recombination." Nucl.Acids Res.26. 988-993 (1998)
[Publications] H.Honda: "Cordiovascular anomaly, impaired action bundling and resistance to Src-induced transformation in mice lacking p130Cas." Nat Genet. 19・4. 361-365 (1998)
[Publications] M.Watanabe: "Purification and Characterization of Wild-type and Mutant“Classical"Nitroreductases of Salmonella typhimurium: L33R mutition greatly diminishes binding of FMN to the nitroreductase of S.typhimunum." J.Biol.Chem.273. 23922-23928 (1998)
[Publications] P.Gruz: "Roles of the mutagenesis proteins Sam A'B and Muc A'B in chemically-induced frameshift mutagenesis in Sarmonella typhimurium hisD3052." Mutat.Res.398. 33-42 (1998)
[Publications] Y.Kukita: "Characterization of GALC gene in three Japanese patients with adult-onset Krabbe disease" Genetic Testing. 1. 217-223 (1998)
[Publications] T.Sasaki: "ATM mutations in AT patients screened by hierarchical strategy" Human Mutation. 12. 186-195 (1998)
[Publications] N.Azuma: "Missense mutation at the C terminus of the PAX6 gene in ocular anterior segment anomalies." Invest.Ophthalmol.Vis.Sci.39. 828-830 (1998)
[Publications] T.Miyashita: "Intracellular aggregate formation of dentatorubral-pallidoluysian atrophy(DRPLA)protein with the extended polyglutamine." Biochem.Biophys.Res.Comm.249. 96-102 (1998)
[Publications] S.Takayama: "Expression and location of Hsp 70/Hsc-binding anti-apototic protein BAG-1 and its variants in normal tissues and tumor cell lines." Cancer Res.58. 3116-3131 (1998)
[Publications] Z.-R.Yuan: "Mutational analysis of the Jagged 1 gene in Aragille syndrome families." Hum.Mol.Genet.7. 1363-1369 (1998)
[Publications] T.Okuyama: "Efficient Fas-ligand gene expression in rodent liver after intra-venous injection of a recombinant adenovirus by the use of a Cre-mediated switching system." Gene Therapy. 5. 1047-1053 (1998)
[Publications] T.Yasuda: "Inhibition of Escherichia coli RecA coprotease activities by DinI." EMBO J.17. 3207-3216 (1998)
[Publications] T.Higuchi: "Polymorphism of the 5'-flanking region of human tumor necrosis factor (TNF)- a gene in Japanese." Tissue Antigens. 51. 605-612 (1998)
[Publications] M.Ikeda M: "Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability." Cancer Res.58. 594-598 (1998)

1998 Fiscal Year Annual Research Report

突然変異の分子病態

Principal Investigator

真木 寿治 奈良先端科学技術大学院大学, バイオサイエンス研究科, 教授 (20199649)

Research Products

[Publications] H.Kasai: "DNA modifications by the mutagen glyoxal : adduction to G and C, deamination of C and GC and GA cross-linking" Carcinogenesis. 19. 1459-1465 (1998)

[Publications] M.Inoue: "Induction of chromosomal gene mutations in Escherichia coli by direct incorporation of oxidatively damaged nucleotides." J.Biol.Chem.273. 11069-11074 (1998)

[Publications] N.Murata-Kamiya: "Nucleotide excision repair proteins may be involved in the fixation of glyoxal-induced mutagenesis in Escherichia coli." Biochem.Biophys.Res.Commun.248. 412-417 (1998)

[Publications] T.Tsuzuki: "Embryonic stem cell gene targeting using bacteriophage λ vectors generated by phage-plasmid recombination." Nucl.Acids Res.26. 988-993 (1998)

[Publications] H.Honda: "Cordiovascular anomaly, impaired action bundling and resistance to Src-induced transformation in mice lacking p130Cas." Nat Genet. 19・4. 361-365 (1998)

[Publications] M.Watanabe: "Purification and Characterization of Wild-type and Mutant“Classical"Nitroreductases of Salmonella typhimurium: L33R mutition greatly diminishes binding of FMN to the nitroreductase of S.typhimunum." J.Biol.Chem.273. 23922-23928 (1998)

[Publications] P.Gruz: "Roles of the mutagenesis proteins Sam A'B and Muc A'B in chemically-induced frameshift mutagenesis in Sarmonella typhimurium hisD3052." Mutat.Res.398. 33-42 (1998)

[Publications] Y.Kukita: "Characterization of GALC gene in three Japanese patients with adult-onset Krabbe disease" Genetic Testing. 1. 217-223 (1998)

[Publications] T.Sasaki: "ATM mutations in AT patients screened by hierarchical strategy" Human Mutation. 12. 186-195 (1998)

[Publications] N.Azuma: "Missense mutation at the C terminus of the PAX6 gene in ocular anterior segment anomalies." Invest.Ophthalmol.Vis.Sci.39. 828-830 (1998)

[Publications] T.Miyashita: "Intracellular aggregate formation of dentatorubral-pallidoluysian atrophy(DRPLA)protein with the extended polyglutamine." Biochem.Biophys.Res.Comm.249. 96-102 (1998)

[Publications] S.Takayama: "Expression and location of Hsp 70/Hsc-binding anti-apototic protein BAG-1 and its variants in normal tissues and tumor cell lines." Cancer Res.58. 3116-3131 (1998)

[Publications] Z.-R.Yuan: "Mutational analysis of the Jagged 1 gene in Aragille syndrome families." Hum.Mol.Genet.7. 1363-1369 (1998)

[Publications] T.Okuyama: "Efficient Fas-ligand gene expression in rodent liver after intra-venous injection of a recombinant adenovirus by the use of a Cre-mediated switching system." Gene Therapy. 5. 1047-1053 (1998)

[Publications] T.Yasuda: "Inhibition of Escherichia coli RecA coprotease activities by DinI." EMBO J.17. 3207-3216 (1998)

[Publications] T.Higuchi: "Polymorphism of the 5'-flanking region of human tumor necrosis factor (TNF)- a gene in Japanese." Tissue Antigens. 51. 605-612 (1998)

[Publications] M.Ikeda M: "Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability." Cancer Res.58. 594-598 (1998)

真木寿治奈良先端科学技術大学院大学, バイオサイエンス研究科, 教授 (20199649)