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Study of Defense Mechanisms against Cellular Damage Caused by Free Radicals

自由基引起细胞损伤的防御机制研究

基本信息

批准号：
11694290
负责人：
NAKABEPPU Yusaku
金额：
$ 5.82万
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：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

For living organisms, the most fundamental biological function is maintaining the integrity of their genomic DNAs harboring the genetic information and transmitting them precisely from cell to cell, as well as from parents to their offsprings. The genomic DNA and its precursor nucleotides, are always in danger of oxidation by free radicals such as superoxide or NO produced during the oxygen respiration and other normal metabolisms. Various oxidized bases and nucleotides are formed in DNA or nucleotide pools by the free radicals, and such oxidative DNA damage may cause mutations or cell death if they are not repaired. Mutations may induce cancers, and cell death may be related to various degenerative disorders such as neurodegenarative diseases.In this project, we have aimed to unveil the molecular mechanisms protecting genomic integrity from damage caused by free radicals. We have been especially focusing on neuronal cell death as a consequence of oxidative damages in non-proliferative cells, as well as on cancer that is believed to be a consequence of such damages in proliferative cells.We have identified and characterized four human enzymes, (1) oxidized purine nucleoside triphosphatase (MTH1), (2) 2-hydroxyadenine/adenine DNA glycosylase (MYH), (3) 8-oxoguanine DNA glycosylase (OGG1), and (4) novel AP endonuclease (APE2). Characterization of knockout mice for each gene revealed that spontaneous accumulation of oxidative DNA damage causes increased occurrence of mutation as well as carcinogenesis. We also found that such oxidative DNA damage accumulates in degenerative neurons along with altered expression of the protective enzymes in patients with neurodegenerative diseases, suggesting that oxidative DNA damage may be involved in neurodegeneration.

对于生物体来说，最基本的生物学功能是保持其基因组DNA的完整性，其中包含遗传信息，并将其精确地从细胞传递到细胞，以及从父母传递到后代。基因组DNA及其前体核苷酸总是处于被氧呼吸和其他正常代谢过程中产生的自由基如超氧化物或NO氧化的危险中。自由基在DNA或核苷酸库中形成各种氧化的碱基和核苷酸，如果不修复，这种氧化DNA损伤可能导致突变或细胞死亡。突变可能诱发癌症，细胞死亡可能与各种退行性疾病（如神经退行性疾病）有关。在本项目中，我们旨在揭示保护基因组完整性免受自由基损伤的分子机制。我们已经鉴定并表征了四种人类酶，（1）氧化嘌呤核苷三磷酸酶（MTH 1），（2）2-羟基腺嘌呤/腺嘌呤DNA糖基化酶（MYH），（3）8-氧代鸟嘌呤DNA糖基化酶（OGG 1），和（4）新的AP内切核酸酶（APE 2）。对每个基因敲除小鼠的表征表明，氧化DNA损伤的自发积累导致突变和致癌发生率增加。我们还发现，这种氧化性DNA损伤沿着神经退行性疾病患者中保护酶表达的改变在退行性神经元中积累，这表明氧化性DNA损伤可能参与神经退行性疾病。