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 损伤是由内源性和外源性以及多种 DNA 自发产生的。 需要修复途径来识别和修复损坏部位。未能修复损伤可能会导致细胞 死亡或突变。随着年龄的增长，体细胞突变会积累并导致多种疾病 包括癌症。我们的长期目标是阐明 DNA 修复酶的分子机制 功能并确定对 DNA 成功至关重要的关键生物物理和生化原理 维修。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，暴露诱发的突变风险， 以及合理改进直接或间接引起基因毒性应激的治疗方法，例如癌症治疗。 该提案将重点关注修复最丰富形式的 DNA 损伤，因为明确的 生物学重要性，并且因为这些是阐明基本原理的优秀 DNA 修复系统模型 这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，因为有机会在特定的背景下立即转化实验结果 疾病和治疗。我们采用跨学科的方法来结合不同类型的结构和 生物物理信息并跨多个时间和尺寸尺度整合信息。这项工作建立在 我们在瞬态动力学方面的核心优势以及严格的结构/活性分析。虽然这个项目的重点 在揭示 DNA 修复的基本生物学机制的过程中，我们将结合多种力量 一群带来独特视角和培训的合作者，使我们能够追求转化和 与特定疾病背景相关的 DNA 修复的临床方面。