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维持其基因组DNA的完整性，其中包含遗传信息并将其在细胞之间以及从父母到后代的精确传递。基因组 DNA 及其前体核苷酸始终面临被氧呼吸和其他正常代谢过程中产生的自由基（例如超氧化物或 NO）氧化的危险。自由基在DNA或核苷酸库中形成各种氧化的碱基和核苷酸，这种氧化性DNA损伤如果不加以修复，可能会导致突变或细胞死亡。突变可能诱发癌症，细胞死亡可能与神经退行性疾病等各种退行性疾病有关。在这个项目中，我们的目的是揭示保护基因组完整性免受自由基损害的分子机制。我们一直特别关注非增殖细胞氧化损伤导致的神经细胞死亡，以及被认为是增殖细胞氧化损伤导致的癌症。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 (MTH1), (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 (OGG1)，和 (4) 新型 AP 核酸内切酶 (APE2)。对每个基因敲除小鼠的表征表明，氧化性 DNA 损伤的自发积累会导致突变和致癌的发生增加。我们还发现，这种氧化性 DNA 损伤会在退行性神经元中积累，同时神经退行性疾病患者中保护性酶的表达也发生改变，这表明氧化性 DNA 损伤可能与神经退行性疾病有关。