Effect of the Spiroiminodihydantoin Lesion on DNA Helix Stability and Nucleosome

螺亚氨基二乙内酰脲损伤对 DNA 螺旋稳定性和核小体的影响

• 批准号: 8100913
• 负责人: Elizabeth Redding Jamieson
• 金额: $ 40.4万
• 依托单位: SMITH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100913
• 关键词: Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Base Pairing; Biological; Biological Process; Cell Aging; Cell Respiration; Cells; Chemistry; Chromatin; DNA; Differential Scanning Calorimetry; Disease; Eukaryotic Cell; Faculty; Female; Fostering; Gelshift Analysis; Genetic; Genetic Materials; Genome; Genomics; Goals; Growth; Guanine; Health; Human; Hydroxyl Radical; Institution; Investigation; Ionizing radiation; Isomerism; Knowledge; Laboratories; Learning; Lesion; Lung Neoplasms; Malignant Neoplasms; Measures; Metals; Mutation; Nucleic Acids; Nucleosomes; Oxidants; Oxygen; Peroxonitrite; Positioning Attribute; Property; Reactive Oxygen Species; Research; Schools; Scientist; Series; Singlet Oxygen; Source; Structure; Thermodynamics; Transition Elements; Water; Woman; adduct; base; career; computer studies; experience; human disease; insight; member; nervous system disorder; oxidation; repair enzyme; repaired; research study; spiroiminodihydantoin; stereochemistry

DESCRIPTION (provided by applicant): Deoxyribonucleic acid (DNA) is the biological molecule within cells that is responsible for transmitting and storing genetic information. Unfortunately, DNA can become damaged, jeopardizing the integrity of this information that is vital for preserving health. Agents that damage DNA, known as reactive oxygen species (ROS), are produced in the normal course of cellular respiration as cells make energy by converting oxygen into water. They can also be introduced by outside sources such as ionizing radiation and certain transition metals. The experiments proposed here will focus on examining a specific type of DNA damage called DNA base oxidation, where the structure of the DNA base, responsible for storing genetic information, is altered. This particular type of DNA damage has been implicated in causing cellular aging, cancer, and neurological disorders like Alzheimer's disease and amyotrophic lateral sclerosis. The goal of this proposal is to investigate the effect of the spiroiminodihydantoin (Sp) lesion on the stability and structure of DNA. This highly-mutagenic lesion, which is formed when ROS react with guanine bases in DNA, produces the same types of mutations found in some human lung tumors. Differential scanning calorimetry (DSC) experiments will be undertaken in Specific Aims 1 & 2 to fully examine the thermodynamic stability of the two different isomeric forms of the Sp lesion in a variety of DNA sequences. The formation and packaging of Sp lesions in nucleosomes will be examined in Specific Aim 3 to investigate the impact of this lesion on eukaryotic cells. The results from these studies will provide important insight into how the biological processing of the Sp lesion in cells contributes to causing diseases like cancer. PUBLIC HEALTH RELEVANCE: Oxidative DNA damage can cause cellular aging, cancer, and neurological disorders. The goal of this proposal is to investigate the effect of a particular type of this damage, known as the spiroiminodihydantoin (Sp) lesion, on the stability and structure of DNA. The results from these studies will provide important insight into how the biological processing of the Sp lesion contributes to causing disease.

描述（由申请人提供）：脱氧核糖核酸（DNA）是细胞内负责传递和储存遗传信息的生物分子。不幸的是，DNA可能会受损，从而危及这些对维护健康至关重要的信息的完整性。破坏DNA的物质，称为活性氧（ROS），是在细胞呼吸的正常过程中产生的，因为细胞通过将氧气转化为水来产生能量。它们也可以通过外部来源引入，例如电离辐射和某些过渡金属。这里提出的实验将集中在检查一种称为DNA碱基氧化的特定类型的DNA损伤，其中负责存储遗传信息的DNA碱基的结构被改变。这种特殊类型的DNA损伤与细胞衰老、癌症和神经系统疾病如阿尔茨海默病和肌萎缩性侧索硬化症有关。 本研究的目的是研究螺亚氨基二乙内酰脲（Sp）损伤对DNA稳定性和结构的影响。当ROS与DNA中的鸟嘌呤碱基反应时形成的这种高度致突变性损伤产生与在一些人类肺肿瘤中发现的相同类型的突变。在特定目标1和2中将进行差示扫描量热法（DSC）实验，以充分检查各种DNA序列中两种不同异构形式的Sp损伤的热力学稳定性。核小体中Sp损伤的形成和包装将在特定目标3中检查，以研究该损伤对真核细胞的影响。这些研究的结果将为细胞中Sp病变的生物学处理如何导致癌症等疾病提供重要的见解。 公共卫生相关性：氧化性DNA损伤可导致细胞衰老、癌症和神经系统疾病。该提案的目的是研究一种特殊类型的这种损伤（称为螺亚氨基二乙内酰脲（Sp）损伤）对DNA稳定性和结构的影响。这些研究的结果将提供重要的见解如何生物处理的Sp病变有助于引起疾病。