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Oxygen-induced DNA damage and its repair mechamism

氧诱导的DNA损伤及其修复机制

基本信息

批准号：
10044304
负责人：
TSUZUKI Teruhisa
金额：
$ 4.48万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10044304/
关键词：
Reactive oxygen Oxidative stress Mutation Carcinogenesis 8-oxo-guanine Tumor suppressor gene DNA repair 2-OH-dATP 8ーオキソグアニン DNA修飾 2ーOH-dATP 活性酵素 β-オキソグアニンアポトーシス神経細胞死

项目摘要

Oxygen radicals, which can be produced through normal cellular metabolism, are thought to play an important role in mutagenesis and tumorigenesis. Among various classes of oxidative DNA damage, 8-oxo-7,8-dihydroguanine (8-oxoG) is most important because of its abundance and mutagenicity.The MTH1 gene encodes an enzyme that hydrolyzes 8-oxo-dGTP to monophosphate in the nucleotide pool, thereby preventing occurrence of transversion mutations. By means of gene targeting, we have established MTH1 gene-knockout cell lines and mice. When examined 18 months after birth, a greater number of tumors were formed in the lungs, livers and stomachs of MTH1-deficient mice, as compared with wild-type mice. The MTH1-deficient mouse will provide a useful model for investigating the role of the MTH1 protein in normal conditions and under oxidative stress.Recent studies showed that the human MTH1 protein hydrolyzed 2-hydroxy-dATP more efficiently and with higher affinity than 8-oxo-dGTP.Current studies on mutagenesis with MTH1-null mutant mice will provide more insight into the role of the sanitizing enzyme, MTH1.We found a single nucleotide polymorphism in human MTH1 gene which alters splicing patterns of its transcripts, and that a novel MTH1 polypeptide with an additional mitochondrial targeting signal is produced from the altered MTH1 mRNA.We further characterized expression and intracellular localization of 8-oxoG DNA glycosylase (OGG1) and 2-OH-A/adenine DNA DNA glycosylase (MYH) in human cells. The authentic OGG1 and MYH proteins present in mitochondria as well as in nuclei, and their intracellular localization were found to be regulated by alternative splicing of each transcript.

氧自由基可以通过正常的细胞代谢产生，被认为在突变和肿瘤发生中起重要作用。在各种类型的DNA氧化损伤中，8-氧-7,8-二氢鸟嘌呤（8-oxoG）因其丰富度和致突变性而最为重要。MTH1基因编码一种酶，可将8-oxo-dGTP水解为核苷酸库中的单磷酸，从而防止逆转突变的发生。通过基因靶向，我们建立了MTH1基因敲除细胞系和小鼠。出生18个月后进行检查时，与野生型小鼠相比，mth1缺陷小鼠的肺、肝脏和胃中形成的肿瘤数量更多。MTH1缺陷小鼠将为研究MTH1蛋白在正常条件和氧化应激下的作用提供一个有用的模型。最近的研究表明，人MTH1蛋白比8-氧- dgtp更有效地水解2-羟基- datp，具有更高的亲和力。目前对MTH1缺失突变小鼠的诱变研究将进一步深入了解消毒酶MTH1的作用。我们发现人类MTH1基因的单核苷酸多态性改变了其转录物的剪接模式，并且从改变的MTH1 mRNA中产生了一种具有额外线粒体靶向信号的新型MTH1多肽。我们进一步鉴定了8-oxoG DNA糖基化酶（OGG1）和2-OH-A/腺嘌呤DNA糖基化酶（MYH）在人细胞中的表达和细胞内定位。真正的OGG1和MYH蛋白存在于线粒体和细胞核中，它们的细胞内定位被发现由每个转录物的选择性剪接调节。