Mechanisms of Base Excision DNA Repair

碱基切除 DNA 修复机制

• 批准号: 10620994
• 负责人: Patrick J O'Brien
• 金额: $ 41.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620994
• 关键词: Age; Base Excision Repairs; Biochemical; Biological; Biophysics; Carcinogens; Cell Death; Cells; Clinical; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Pathway; Disease; Enzymes; Exposure to; Failure; Genetic; Genotoxic Stress; Genotype; Goals; Human; Kinetics; Malignant Neoplasms; Modeling; Molecular; Mutagenesis; Mutation; Phenotype; Risk; Site; Somatic Mutation; Source; Structure; System; Time; Training; Translating; Work; base; cancer therapy; genome integrity; improved; interdisciplinary approach; repaired

Abstract: DNA damage arises spontaneously from endogenous and exogenous sources and multiple DNA repair pathways are required to identify and repair sites of damage. Failure to repair damage can result in cell death or mutations. Somatic mutations accumulate as we age and result in a wide spectrum of diseases including cancer. Our long-term goal is to elucidate the molecular mechanisms by which DNA repair enzymes function and identify the key biophysical and biochemical principles that are important for successful DNA repair. A fundamental understanding of DNA repair enzymes is immensely valuable as it provides a framework for understanding the relationships between genotype and phenotype, exposure-induced mutagenesis risks, and in rationally improving treatments that directly or indirectly cause genotoxic stress, such as cancer therapy. This proposal will focus on repair of the most abundant forms of DNA damage both because of the clear biological importance, and because these are excellent model DNA repair systems to elucidate basic principles that may be applied broadly to understanding many DNA repair pathways. We will primarily focus on human enzymes because of the opportunities to immediately translate experimental findings in the context of specific diseases and treatments. We take an interdisciplinary approach to combine different types of structural and biophysical information and to integrate information across multiple time and size scales. This work builds upon our core strength in transient kinetics with rigorous structure/activity analysis. Although the focus of this project is in uncovering the fundamental biological mechanisms for DNA repair, we will combine forces with a diverse set of collaborators who bring unique perspective and training that will allow us to pursue translational and clinical aspects of DNA repair that pertain to specific disease contexts.

摘要：DNA损伤可自发发生于内源性和外源性DNA， 需要修复途径来识别和修复损伤部位。如果不能修复损伤， 死亡或突变。随着年龄的增长，体细胞突变不断积累，导致各种疾病 包括癌症我们的长期目标是阐明DNA修复酶的分子机制， 功能，并确定关键的生物物理和生物化学原则，是成功的DNA 修复.对DNA修复酶的基本了解非常有价值，因为它提供了一个框架， 为了了解基因型和表型之间的关系，诱变风险， 以及合理改进直接或间接引起遗传毒性应激的治疗，如癌症治疗。 这项建议将集中在修复最丰富的形式的DNA损伤，这既是因为明确的 生物学的重要性，因为这些是很好的模型DNA修复系统，以阐明基本原则， 可以广泛应用于理解许多DNA修复途径。我们将主要关注人类 酶，因为有机会立即翻译实验结果的背景下，具体的 疾病和治疗。我们采取跨学科的方法，将联合收割机不同类型的结构和 生物物理信息和整合跨多个时间和大小尺度的信息。这项工作建立在 我们在瞬态动力学和严格的结构/活性分析方面的核心优势。虽然这个项目的重点 在揭示DNA修复的基本生物学机制中，我们将联合收割机与各种不同的 一组合作者，他们带来了独特的视角和培训，使我们能够追求翻译和 与特定疾病背景相关的DNA修复的临床方面。