HYDROLYTIC AND FREE RADICAL MEDIATED DNA DAMAGE

水解和自由基介导的 DNA 损伤

• 批准号: 2759804
• 负责人: Lawrence C Sowers
• 金额: $ 22.59万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-01-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2759804
• 关键词: 5 methylcytosine; DNA damage; carcinogens; chemical kinetics; free radicals; hydrolysis; mutagens; oxidation; purines

DESCRIPTION: A growing body of evidence suggests that endogenous damage to DNA may contribute significantly to genomic instability, human disease and aging. An understanding of the formation and persistence of endogenous DNA damage is also required in order to assess the impact of DNA damage induced by exogenous mutagens and carcinogens.The purpose of the work described in this proposal is to investigate several components of endogenous DNA damage. Endogenous damage to DNA may result from either hydrolysis or oxidation of DNA and its components. Among the purines, hydrolysis resulting in the abasic sites and oxidation to form 8-oxopurines have dominated the literature. Purines may also be damaged by imidazole ring-opening generating formamidopyrimidine (FAPY) derivatives via both hydrolysis and oxidation. Hydrolytic formation of FAPY derivatives has received minimal attention in the literature. The kinetics of purine hydrolysis must be understood in order to assess accurately the significance of FAPY derivatives.The preliminary results from Dr. Sowers' laboratory indicate that current and often reported measurements of FAPY derivatives may yield extreme underestimates of the actual levels. Similarly, hydrolysis of the oxopurines may be biologically significant, and can lead to erroneous quantitation of oxidation damaged products. Oxidation of thymidine generating 5- hydroxymethyl-2'-deoxyuridine (HMdU) is a frequent DNA lesion. HMdU is controversial in terms of both amount formed and biological significance. Dr. Sowers' laboratory has identified chemical characteristics of HMdU which may explain the divergent quantitative reports. The investigators propose a series of experiments which should shed light on the potential biological impact of HMdU formation in DNA. In parallel with the oxidation of the thymine methyl group, they present preliminary data showing that the methyl group of 5-methylcytosine is also a target for oxidative damage. The oxidative damage to 5- methylcytosine is relatively unexplored. Because of the pivotal role of cytosine methylation in gene control, oxidation of 5mC may be part of an unrecognized mechanism for inappropriate activation of oncogenes and latent viral genes.

描述：越来越多的证据表明，内源性损害 人类基因组的不稳定性可能会对DNA产生重大影响 疾病和衰老。对形成和坚持的理解 为了评估影响，还需要对内源性DNA损伤进行评估 外源诱变剂和致癌物引起的DNA损伤。目的 这项提案中描述的工作之一是调查几个 内源性DNA损伤的成分。可能导致DNA内源性损伤 脱氧核糖核酸及其成分的水解性或氧化性。其中 嘌呤，导致碱性位的水解和氧化 八年级--恶口嘌呤类药物主导了文学。嘌呤也可能是 咪唑开环生成甲酰胺基嘧啶(Fapy)造成的损伤 通过水解物和氧化物制得衍生物。水解性形成 Fapy衍生品在文献中只得到了很少的关注。这个 必须了解嘌呤的水解动力学才能评估 准确理解Fapy导数的意义。初步结果 来自索沃斯博士实验室的研究表明，目前和经常报道的 对Fapy衍生品的测量可能会产生对 实际水平。类似地，氧嘌呤的水解物可以是 具有生物学意义，并可能导致错误的量化 氧化损坏的产品。胸腺嘧啶核苷的氧化生成5- 羟甲基-2‘-脱氧尿苷(HMdU)是一种常见的DNA损伤。HMdU是 在形成的数量和生物学上都有争议 意义。索沃斯博士的实验室已经发现了化学物质 HMdU的特征可以解释数量上的差异 报告。调查人员提出了一系列实验，这些实验应该 阐明了DNA中形成HMdU的潜在生物学影响。 在胸腺嘧啶甲基氧化的同时，它们还存在 初步数据显示，5-甲基胞嘧啶的甲基是 也是氧化损伤的目标。对5-羟色胺的氧化损伤 甲基胞嘧啶相对来说是未被开发的。因为它的关键作用 胞嘧啶甲基化在基因控制中，5mC的氧化可能是一部分 一种未知的癌基因不适当激活机制 和潜伏的病毒基因。