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

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） 将对寡脱氧核苷酸进行结构研究， 用氯乙烯代谢物的特定加合物改性 氯环氧乙烷和氯乙醛，以及α，β-不饱和 醛类丙烯醛、巴豆醛和羟基壬烯醛。内收部位 将是鸟嘌呤的N1、N2和N3位置， 腺嘌呤和胞嘧啶的N3和N4位置。我们的目标是 不同类别的环状加合物之间的化学差异，以及 链内和链间交联，具有结构和构象 DNA中的属性反过来，在此过程中获得的结构信息 第二个项目的生物数据将与第二个项目的生物数据相关联。乙烯基 氯化物代谢物增加了C2单元，而丙烯醛、巴豆醛和 羟基壬基酚将C3单元添加到DNA碱基。一类环加合物 被检查的被称为“远端”加合物。在这些化合物中， 羟基乙醇或羟基丙醇环外加合物位于邻近 氨基氮。这些被假定为对DNA具有高度破坏性 结构，因为它们干扰沃森-克里克碱基配对。研究将 为了了解DNA双链体如何容纳这些 扭曲另一类要研究的环状加合物称为 “近端”加合物，其中环状羟基乙醇或环己基的羟基基团是“近端”加合物， 羟基丙烷加合物与亚氨基氮相邻。为这些 可以预期的是，其中单齿加合物 连接在氨基氮上的双链体DNA将稳定在双链体DNA中。努力将 重点是了解双链体DNA如何调节这个位置， 平衡，以及作为开环产物的醛是如何 由DNA双链体容纳。这一点很重要，因为一旦醛 形成，具有交联DNA的潜力。位点特异性的结构 第二个项目中确定的DNA交联将被检查， DNA序列在控制交联中的作用连接体长度的作用 (C2相对于C3）的交联能力和所产生的变形 还将检查通过交联引入双链体DNA的分子。