DNA氧化损伤修复基因HOGG1低表达细胞株的建立及其应用研究

发布时间：2018-01-07 02:00

本文关键词：DNA氧化损伤修复基因HOGG1低表达细胞株的建立及其应用研究　出处：《四川大学》2005年博士论文　论文类型：学位论文

【摘要】：DNA损伤与修复一直是毒理学和肿瘤学研究的热点,在众多DNA损伤中,以自由基(free radical)引起的DNA氧化损伤(oxidative DNA damage)研究最多,被认为是启动和促进肿瘤发生最为重要的因素。大量研究表明:活性氧(reactive oxygen species,ROS)自由基可以直接攻击生物大分子DNA,诱发DNA链断裂和多种形式的碱基修饰。在各种DNA氧化损伤中,以鸟嘌呤8位碳原子的氧化最常见,其氧化产物8-羟基-脱氧鸟嘌呤(7,8-dihydro-8-oxoguanine,8-OHdG)在体内形成后较为稳定、易于检测,被公认为DNA氧化损伤的生物标志物(biomarker)。此外,8-OHdG最特征、最具生物学意义的危害是:DNA链中的鸟嘌呤G被氧化成8-OHdG后可导致DNA链空间构象的改变,在DNA合成时8-OHdG优先或等效率地与腺嘌呤A配对,从而导致DNA链G:C→T:A颠换,该颠换在肿瘤形成中发生最早,常见于癌基因ras和抑癌基因p53中,故此突变被认为与肿瘤的发生发展、机体细胞的老化和某些退行性疾病的发生都具有密切的关系。人体细胞中,特异性切除和修复8-OHdG的酶是8-羟基鸟嘌呤DNA糖苷酶(human 8-oxoguanine DNA glycosylase,简称HOGG1),具有切除DNA双链中与碱基C配对的8-OHdG的作用,从而恢复基因组中正常的G∶C配对,在维持基因组稳定和肿瘤预防上具有举足轻重的作用,编码该蛋白的基因hOGG1于1997年成功克隆。人群流行病学研究显示:hOGG1基因在不同人群存在遗传多态性,并与癌症易感性密切相关,其突变或缺失将增加个体罹患肿瘤的风险。
[Abstract]:DNA damage and repair has been a hotspot in toxicology and oncology, in numerous DNA injury by free radicals (free, radical) DNA caused oxidative damage (oxidative DNA damage) of the most, is thought to initiate and promote tumorigenesis of the most important factors. A large number of studies have demonstrated that reactive oxygen species (reactive oxygen, species ROS), free radicals can attack the biological macromolecules DNA induced DNA strand breaks and base modification in various forms. In a variety of oxidative DNA damage, the most common of the 8 carbon atom of guanine oxidation, the oxidation products of 8- hydroxy desoxyguanosine (7,8-dihydro-8-oxoguanine, 8-OHdG) in the body after the formation of relatively stable, easy to detect that is recognized as a biomarker of oxidative DNA damage (biomarker). In addition, the characteristics of 8-OHdG, the most harmful biological significance is: DNA in the chain of guanine G by oxygen into 8-OHdG can lead to DNA chain Between the conformational change in the synthesis of DNA 8-OHdG and other priority or efficiently paired with adenine A, resulting in DNA chain G:C to T:A transversion, the transversion in tumor formation in the earliest, common in cancer gene Ras and tumor suppressor gene p53, this mutation is considered with the occurrence and development of tumor, are there is a close relationship between occurrence of cellular aging and certain degenerative diseases.
In human cells, specific excision and repair of 8-OHdG enzyme is 8- oxoguanine DNA glycosylase (human 8-oxoguanine DNA glycosylase, referred to as HOGG1), with DNA double chain excision and base pairing of C 8-OHdG, thus restoring G: normal genome C pairing, plays an important role in maintaining genomic stability and the prevention of cancer, hOGG1 gene encoding the protein was successfully cloned in 1997.
Epidemiological studies show that hOGG1 gene is polymorphic in different populations, and is closely related to cancer susceptibility. Mutation or deletion will increase the risk of cancer.

【学位授予单位】：四川大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R346

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