Mechanisms of Nucleic Acid Oxidation and Cross-linking

这项工作的目的是了解DNA-蛋白质交联形成所涉及的化学。 DNA片段的单电子氧化在许多核苷上产生自由基阳离子，然后被蛋白质亲核试剂捕获。 然后，蛋白质-DNA加合物将通过包括NMR和LC-ESI-MS/MS在内的许多光谱技术进行表征。最后，将合成40 mer DNA序列及其互补序列。 该序列包含一个三重G轨道、一个双G轨道和几个与GC对互补的AT轨道。 然后使用已经掺杂有10%OG（氧化的G）的G前体制备该链，导致OG在链中的所有10个G位置中的随机分布和平均10 G/链。 这些链与胺和蛋白质亲核试剂的反应以及随后的加合物的表征将用于识别最容易在氧化损伤后形成加合物的“热点”序列。有了这个奖项，有机和高分子化学计划是支持博士辛西娅J.伯罗斯的化学系在犹他州大学的研究。 Burrows博士将探索蛋白质与被氧化化学反应破坏的DNA片段的反应。 揭示氧化性DNA损伤所涉及的化学反应对于从分子水平上理解衰老、癌症和许多神经系统疾病所涉及的化学过程非常重要。 由于在这个项目上工作的结果培训的学生将获得机械有机化学以及生物化学的经验，因此他们将拥有生物技术和制药行业所需的技能。

The objective of this work is to understand the chemistry involved in the formation of DNA-protein cross links. One electron oxidation of DNA fragments generates radical cations at a number of nucleosides which are then trapped by protein nucleophiles. The protein-DNA adducts will then be characterized by a number of spectroscopic techniques including NMR and LC-ESI-MS/MS. Lastly, a 40 mer DNA sequence, and its complement, will be synthesized. This sequence contains a triple G track, a double G and several AT tracks which compliment GC pairs. This strand will then be prepared using G precursors which have been doped with 10% OG (oxidized G) leading to a random distribution of OG in all 10 G positions in the strand and an average of 1 OG/strand. Reactions of these strands with amine and protein nucleophiles and characterization of the subsequent adducts will be used to identify "hot spot" sequences which are most susceptible to adduct formation following oxidative damage. With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Cynthia J. Burrows of the Department of Chemistry at the University of Utah. Dr. Burrows will explore the reactions of proteins with DNA fragments which have been damaged by oxidative chemical reactions. Uncovering the chemical reactions involved in oxidative DNA damage is important to a fundamental molecular understanding of the chemical processes involved in aging, cancer and a number of neurological disorders. Students trained as a result of working on this project will gain experience in mechanistic organic chemistry as well as biochemistry, hence they will have skills needed by both the biotechnology and pharmaceutical industries.