HYDROLYTIC AND FREE RADICAL MEDIATED DNA DAMAGE

描述：越来越多的证据表明， 对DNA的影响可能会显着影响基因组的不稳定性， 疾病和衰老。 对形成和持续的理解 内源性DNA损伤也需要，以评估影响 外源性诱变剂和致癌物引起的DNA损伤的研究 本提案中描述的工作之一是调查几个 内源性DNA损伤的成分。 DNA的内源性损伤可能导致 DNA及其组分的水解或氧化。 之间 嘌呤，水解导致脱碱基位点和氧化， 形式8-氧代嘌呤已经占据了文献。 嘌呤也可以是 通过咪唑开环产生甲酰胺基嘧啶（FAPY） 衍生物通过水解和氧化。 水解形成 FAPY衍生物在文献中受到的关注最少。 的 必须了解嘌呤水解的动力学， 准确的FAPY衍生物的意义。初步结果 来自Sowers博士实验室的研究表明， FAPY衍生物的测量可能会产生极端低估 实际水平。 类似地，氧代嘌呤的水解可以是 生物学意义，并可能导致错误的定量 氧化破坏产品。 氧化胸苷产生5- 羟甲基脱氧尿苷（HMdU）是一种常见的DNA损伤。 HMdU是 在形成的数量和生物学方面都有争议 意义 索沃斯博士的实验室已经鉴定出 HMdU的特征可以解释不同的定量 报道 研究人员提出了一系列实验， 揭示了DNA中HMdU形成的潜在生物学影响。 与胸腺嘧啶甲基的氧化平行， 初步数据表明，5-甲基胞嘧啶的甲基是 也是氧化损伤的目标。 5-羟色胺的氧化损伤 甲基胞嘧啶是相对未开发的。 因为它的关键作用 胞嘧啶甲基化的基因控制，氧化5 mC可能是部分 一种未被认识的致癌基因不适当激活的机制 和潜伏的病毒基因。

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.