Biological phenomena caused by 8-oxoguanine in DNA

DNA中8-氧代鸟嘌呤引起的生物现象

• 批准号: 12680814
• 负责人: SAKUMI Kunihiko
• 金额: $ 2.56万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12680814/
• 关键词: gene-disrupted mouse; ogg1 gene; 8-oxoguanine; mutation; lung tumor; mth1 gene

Among the oxidized molecules caused by reactive oxygen spices, 8-oxoguanine (8-oxoG) is mutation prone molecule as it pairs with adenine as well as cytosine during DNA replications, resulting in transversion mutations. 8-Oxoguanine-DNAglycosylase, encoded by the ogg1 gene, removes the oxidized base from DNA. Another enzyme, 8-oxo-dGTPase that is the mthl gene product, degrades an oxidized DNA precursor, 8-oxo-dGTP into 8-oxo-dGMP and pyrophosphate. To evaluate the role of each enzyme in prevention of tumorigenesis, we produced the knockout mice for oggl and mth1 genes.Lung adenoma/carcinoma was spontaneously developed in the ogg1 knockout mice about 1.5 year after birth. The lung tumor associated with ogg1 knockout genotype was suppressed by an additional mutation of the mth1 gene which encodes another 8-oxoguanine excluding enzyme, 8-oxo-dGTPase. To obtain the mice with four kinds of genotypes, the mth1+/+, ogg1+/+, the mth1-/-, ogg1+/+, the mth1+/+, ogg1-/-, and the mth1-/-, ogg1-/-, … More the mth1+/-, ogg1+/+ male was crossed with the mth1+/+, ogg1+/- female to produce mth1+/-, ogg1+/- mice. From the progenies resulted by inbreeding the mice, we selected the mice with four kinds of genotype for a spontaneous tumorigenesis experiment. The mice were grown under the special pathogen free condition, and examined at 580(±1) days after birth, for spontaneously developed tumors. Six out of 14 mth1+/+, ogg1-/- mice carried lung adenoma/carcinoma, and some of the mice have numbers of tumors in the different lobi. The mean number of tumors per mouse is 0.71, which is 5 times more than that of the wild type mouse (0.14). We obtained a similar result from a different experiment using the ogg1+/+ and the ogg1-/- mice examined between 69 and 75 weeks after birth. The latter experiment also showed that there is little difference in numbers of liver and intestinal tumors between the groups. Since there are reports that mutations exist in ogg1 gene in the human lung cancer, the ogg1 should act as a lung tumor suppressor gene in mammalians. Less

在由活性氧香料引起的氧化分子中，8-氧气（8-oxog）是突变的易于分子，因为ITHIRS伴随着DNA复制过程中的ITHIR和INE，从而导致横向突变酶。基因，从另一个酶，8-氧气-DGTPase（MTHL基因产物）降解为8-oxo-dgmp和pyrophathate，以评估每个酶在肿瘤中的作用，我们产生了敲门敲门物。 OGGL和MTH1基因的小鼠在出生后约1.5年以OGG1敲除小鼠的形式自发地形成了与MTH1相关的肺部肿瘤具有四种基因型+/+，mth1 - / - ，ogg1+/+，mth1+//////+，ogg1 - / - 和mth1 - / - ，ogg1-/ - ， - 更多mth1+/更多+雄性与MTH1+/+，OGG1 +/-女性产生Mth1 G1+///-鼠标的+小鼠产生的MTH1 +/-在特殊病原体的条件下生长，并在出生后580天（±1）开始研究肿瘤中的六个。在野生型小鼠中，我们使用OGG1+进行了不同的经验，而OGG1在出生后69至75周之间进行了。组。

项目成果

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Tsuchimoto, D. 等人：“人 APE2 蛋白主要定位于细胞核，因此在一定程度上定位于线粒体，而核 APE2 部分与增殖细胞核抗原相关”Nucleic Acids Res.. 29. 2349-2360 (2001

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Nakabeppu, Y. et al.: "Mechanisms protecting genomic integrity from damage caused by reactive oxygen species : Implications for carcinogenesis and neurodegeneration"Environ. Mutagen Res.. 23. 182-195 (2001)

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