HYDROLYTIC AND FREE RADICAL-MEDIATED DNA DAMAGE

水解和自由基介导的 DNA 损伤

• 批准号: 2188124
• 负责人: Lawrence C Sowers
• 金额: $ 14.54万
• 依托单位: CITY OF HOPE NATIONAL MEDICAL CENTER
• 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 1996-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2188124
• 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 对DNA可能会对基因组不稳定性产生重大贡献 疾病和衰老。 对形成和持久性的理解 为了评估影响，还需要内源性DNA损伤 外源诱变剂和致癌物引起的DNA损伤的目的 该提案中描述的工作是调查几个 内源性DNA损伤的成分。 内源性损害DNA可能会导致 来自DNA及其成分的水解或氧化。 之中 嘌呤，水解导致无碱性部位，氧化为 8-氧嘌呤的形式主导了文献。 嘌呤也可能是 受咪唑开环产生甲米酰咪定（FAPY）的损害 通过水解和氧化衍生物。 水解形成 Fapy衍生物在文献中受到了最少的关注。 这 必须了解嘌呤水解的动力学，以评估 准确的Fapy衍生物的意义。 从Sowers博士的实验室中，表明当前并经常报告 Fapy衍生物的测量可能会引起极端低估的 实际级别。 同样，氧化钠的水解可能是 具有生物学意义，并可能导致错误的定量 氧化损坏的产品。 胸苷产生5-的氧化 羟甲基-2'-脱氧尿苷（HMDU）是常见的DNA病变。 HMDU是 就形成和生物学的数量而言有争议 意义。 Sowers博士实验室已经确定了化学 HMDU的特征可以解释定量的不同 报告。 调查人员提出了一系列的实验 阐明了HMDU形成在DNA中的潜在生物学影响。 与胸腺甲基的氧化并行，它们存在 初步数据表明，5-甲基霉素的甲基是 也是氧化损伤的目标。 5-的氧化损伤 甲基胞嘧啶相对未探索。 由于角色关键 基因对照中的胞嘧啶甲基化，5MC的氧化可能是部分 一种无法识别的机制，用于不适当激活癌基因 和潜在病毒基因。