BASE-PAIRING & STACKING PROPERTIES OF 8-HYDROXYGUANINE

碱基配对

• 批准号: 2183638
• 负责人: Peter M. Gannett
• 金额: $ 10.02万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2183638
• 关键词: DNA damage; chemical carcinogen; chemical structure function; conformation; deoxyguanosine; guanine; hydroxylation; nuclear magnetic resonance spectroscopy; nucleic acid structure; oligonucleotides; radiation carcinogen

8-Hydroxydeoxyguanine (8-OHdG) is a DNA base alteration resulting from oxidative damage. This adduct has been shown to result from radiation damage and rom exposure to a variety of chemical carcinogens. Significantly, 8-OHdG preferentially forms in the target organs of certain carcinogens and its incorporation into DNA templates causes mis-reading. These and other data have lead to the proposal that the 8-OHdG, by analogy to other base modifications, are due to changes in both base-pairing and base-stacking properties since conversion of dG to 8-OHdG results in changes in base glycosidic bond angle torsion, 8-OHdG bears a proton on N7, and the imidazole ring's electronic environment is drastically altered. Therefore, the purpose of this proposal is to determine the base-pairing and base-stacking properties of 8-OHdG. The base/sugar geometry and the presence of an N7-proton in 8-OHdG suggest that 8-OHdG may for Hoogsteen base-pairs. To examine this, NMR techniques will be used to study the base-pairing properties of 8-OHdG with deoxycytosine (dC) and mis-matches with deoxyadenonsine (dA) and deoxythymidine (dT). The use of monomers minimizes contributions from base-stacking. In addition, the base-pairing properties of 8- methoxydeoxyguanine (8-OMedG), which has the same base/sugar geometry but no N7-proton, will be examined to assess the importance of the N7-proton of 8-OHdG. Base-stacking interactions will be examined to assess the importance of the N7-proton of 8-OHdG. The usual techniques will be applied and include correlation spectroscopy (COSY), NOE and NOESY 2-D NMR. Alterations in base-stacking are expected due to changes in the electronic environment about the imidazole ring of 8-OHdG. Modification of the base- pairs at adjacent sites and local and/or global geometry may also be observed. These studies will determine the changes in base-pairing and base-stacking of and caused by 8-OHdG relative to dG. Insight into the relationship of these factors and the mutagenic nature of 8-OHdG will be gained. These studies will also provide a foundation for future studies including base- pair "mis-matches" between 8-OHdG and bases other that dC, the sequence dependence of alterations in base-stacking interactions, base-pairing and base-stacking computation studies. These studies also provide data of general interest regarding the factors which control DNA conformation.

8-羟基脱氧鸟嘌呤（8-OHdG）是一种DNA碱基改变， 氧化损伤 这种加合物已被证明是由辐射引起的 损害和ROM暴露于各种化学致癌物。 值得注意的是，8-OHdG优先在某些肿瘤的靶器官中形成， 致癌物质和它的掺入DNA模板导致误读。 这些和其他数据导致了这样的建议，即8-OHdG，通过类推， 其他碱基修饰，是由于碱基配对和 碱基堆积性质，因为dG转化为8-OHdG导致 碱基糖苷键角扭转的变化，8-OHdG在N7上带有一个质子， 并且咪唑环的电子环境被彻底改变。 因此，本建议的目的是确定碱基配对 和8-OHdG的碱基堆积性质。 碱基/糖的几何结构和8-OHdG中N7质子的存在表明 8-OHdG可能形成Hoogsteen碱基对。 为了验证这一点，核磁共振技术 将用于研究8-OHdG与 脱氧胞嘧啶（dC）和与脱氧腺苷（dA）的错配， 脱氧胸苷（dT）。 单体的使用最大限度地减少了 垒叠 此外，8- 甲氧基脱氧鸟嘌呤（8-OMedG），其具有相同的碱基/糖几何结构，但 没有N7-质子，将进行检查，以评估N7-质子的重要性， 8-OHdG。 将检查碱基堆积相互作用，以评估 8-OHdG的N7-质子的重要性。我们将采用常规技术 包括相关谱（COSY）、NOE和NOESY二维NMR。 由于电子设备的变化， 8-OHdG的咪唑环周围的环境。 基地改造- 在相邻位置处的对以及局部和/或全局几何形状也可以 观察 这些研究将确定碱基配对和碱基堆积的变化 由8-OHdG相对于dG引起。 深入了解 这些因素和8-OHdG的致突变性。 这些 研究还将为未来的研究提供基础，包括基础- 8-OHdG和dC以外的碱基之间的配对“错配”， 依赖于碱基堆积相互作用、碱基配对和 基础叠加计算研究。 这些研究还提供了 关于控制DNA构象的因素的普遍兴趣。

项目成果

Vitamin B6 and cancer: synthesis and occurrence of adenosine-N6-diethylthioether-N-pyridoximine-5'-phosphate, a circulating human tumor marker.

维生素 B6 与癌症：腺苷-N6-二乙基硫醚-N-吡哆肟-5-磷酸（一种循环人类肿瘤标志物）的合成和发生。

• 发表时间: 1996
• 期刊: Cancer research.
• 作者: Tryfiates,GP;Gannett,PM;Bishop,RE;Shastri,PK;Ammons,JR;Arbogast,JG
• 通讯作者: Arbogast,JG