CONFORMATIONAL STUDIES OF ADDUCTED OLIGODEOXYNUCLEOTIDES

加合寡脱氧核苷酸的构象研究

• 批准号: 6647788
• 负责人: Michael P Stone
• 金额: $ 10.78万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6647788
• 关键词: DNA; DNA damage; adduct; chemical carcinogen; conformation; crosslink; heterocyclic polycyclic compound; nuclear magnetic resonance spectroscopy; nucleic acid structure; oligonucleotides; DNA; DNA damage; adduct; chemical carcinogen; conformation; crosslink; heterocyclic polycyclic compound; nuclear magnetic resonance spectroscopy; nucleic acid structure; oligonucleotides

DESCRIPTION (provided by applicant) Structural studies will be conducted on oligodeoxynucleotides site-specifically modified with specific adducts of the vinyl chloride metabolites chlorooxirane and chloroacetaldehyde, and the alpha, beta-unsaturated aldehydes acrolein, crotonaldehyde, and hydroxynonenal. The adduction sites will be the N1, N2, and N3 positions of guanine, the N1 and N6 positions of adenine, and the N3 and N4 positions of cytosine. The goal is to correlate differences in chemistry between different classes of cyclic adducts, and intra- and inter-strand crosslinks, with structural and conformational properties in DNA. In turn, the structural information derived in this project will be correlated with biological data from the second Project. Vinyl chloride metabolites add a C2 unit, whereas acrolein, crotonaldehyde, and hydroxynonerial add a C3 unit to the DNA base. One class of cyclic adducts to be examined are termed "distal" adducts. In these, a hydroxy group in the hydroxy ethano or hydroxy propano exocyclic adduct is positioned adjacent to an amino nitrogen. These are postulated to be highly disruptive to DNA structure because they interfere with Watson-Crick base pairing. Studies will be geared towards understanding how the DNA duplex accommodates these distortions. Another class of cyclic adducts to be examined are termed "proximal" adducts, in which a hydroxy group of the cyclic hydroxy ethano or hydroxy propano adduct is positioned adjacent to an imino nitrogen. For these it is anticipated that the ring-opened form in which the monodentate adduct is attached at the amino nitrogen will be stabilized in duplex DNA. Effort will focus on understanding how duplex DNA modulates the position of this equilibrium, and how the aldehyde that is the product of ring-opening is accommodated by the DNA duplex. This is important because the aldehyde, once formed, has the potential to crosslink the DNA. The structures of site-specific DNA crosslinks identified in the second Project will be examined, as will the role of DNA sequence in controlling crosslinking. The role of linker length (C2 versus C3) on the ability to crosslink and the resulting distortions introduced into duplex DNA by the crosslinks will also be examined.

描述（由申请人提供） 结构研究将在特定于寡脱氧核苷酸的位点上进行 用特定的乙烯基氯化物代谢物修饰 氯乙烷和氯乙醛醛，以及α-不饱和的alpha 醛，克罗托纳醛和羟基苯胺。收缩地点 将是鸟嘌呤的N1，N2和N3位置，N1和N6位置 腺嘌呤以及胞嘧啶的N3和N4位置。目标是关联 不同类别的循环加合物之间的化学差异， 内和跨链路交联，具有结构和构象 DNA中的性质。反过来，在此得出的结构信息 项目将与第二个项目的生物数据相关。乙烯基塑料 氯化物代谢物增加了一个C2单元，而丙烯醛，双醛和 羟基对DNA碱基添加C3单元。一类循环加合物 被检查称为“远端”加合物。在其中，一个羟基 羟基乙醇或羟基丙诺丙旋脱旋转加合物位于邻近的位置 氨基氮。这些被认为对DNA高度破坏 结构是因为它们会干扰Watson-Crick基座配对。研究将 旨在了解DNA双链体如何适应这些 扭曲。另一类要检查的循环加合物被称为 “近端”加合物，其中一组环状羟基乙醇或 羟基丙烷加合物位于伊米诺氮的附近。为此 预计单端加合物为 附着在氨基氮将在双链DNA中稳定。努力会 专注于了解双工DNA如何调节该位置 平衡，以及开环产物的醛如何 由DNA双链体容纳。这很重要，因为醛一次 形成的，具有交联DNA的潜力。特定地点的结构 将检查第二个项目中确定的DNA交联，将进行检查， DNA序列在控制交联中的作用。接头长度的作用 （C2对C3）交联能力和结果失真 还将检查通过交叉链接引入双链DNA。