Structural and Mechanistic Studies of DNA Repair

DNA修复的结构和机制研究

基本信息

  • 批准号:
    10247705
  • 负责人:
  • 金额:
    $ 38.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

Oxidative stress is a prevalent and dangerous cellular condition resulting in deleterious modifications to the structure of DNA. These modifications promote mutagenesis and consequently the development of numerous human maladies, including cancer. The base excision repair (BER) pathway is the cells primary defense against oxidative DNA damage and is a vital guardian of genome stability. While the roles of individual enzymes during a classical BER cycle are largely established, it remains enigmatic how these enzymes function together in a multi-protein/DNA complex to facilitate the channeling of toxic DNA repair intermediates between each protein. In addition, it is poorly understood how deviations in the classical BER pathway affect the DNA repair process and genome stability. These deviancies range from mismatched-, damaged-, and ribo-nucleotides inserted by a DNA polymerase, to the coordinated repair of “dirty” or damaged DNA ends that block BER. These scenarios become particularly biologically relevant during times where there is an increase in genome instability (i.e., in cancer cells and/or during therapeutic treatments). The overarching goal of this proposal is to understand the molecular mechanisms of each BER component individually and to place these activities within the larger BER co-complex with damaged DNA repair intermediates. Elegant biophysical approaches are required to elucidate these BER complexities and to provide both a foundation for interpreting the biological response and the subsequent development of therapeutic treatments. We are in a unique position to advance this scientific front based on my strong track record in DNA damage and repair, assembled team of collaborators, and multidisciplinary approach. To meet this goal, we utilize a comprehensive approach of time-lapse X-ray crystallography, neutron crystallography, small angle neutron scattering, molecular dynamic simulations, enzyme kinetics, and single-molecule total internal reflection microscopy. Using these methodologies, we will determine 1) How the location of DNA damage alters the DNA polymerase mechanism during repair; 2) How does the poorly characterized APE1 exonuclease reaction process damaged RNA and DNA repair blocks; 3) What are the mechanistic roles of protons during DNA damage and repair; 4) How are DNA repair complexes formed and structurally organized? This set of questions will go from an atomic level mechanistic understanding of key BER components to the structural and dynamic interactions within the entire BER multi-protein complex. By doing this, we will lay the foundation to address an inherent challenge in establishing cellular models and developing new therapeutic treatments that target DNA repair. With this information in hand, we will be closer to our long-term goal of providing a basis for rational drug design towards the development of more effective chemotherapeutics and synergistic drug combinations that target proteins involved in the DNA damage response.
氧化应激是一种普遍的和危险的细胞状况,导致对细胞的有害修饰。 DNA的结构。这些修饰促进了诱变,并因此促进了许多突变体的发展。 包括癌症在内的人类疾病。碱基切除修复(BER)途径是细胞对DNA的主要防御途径。 氧化DNA损伤,是基因组稳定性的重要监护人。虽然单个酶的作用, 经典的BER循环基本上已经建立,但这些酶如何在一个特定的环境中一起发挥作用仍然是个谜。 多蛋白质/DNA复合物,以促进每个蛋白质之间的毒性DNA修复中间体的通道。 此外,人们对经典BER途径中的偏差如何影响DNA修复过程知之甚少 和基因组稳定性。这些异常的范围从错配的,损坏的,和核糖核苷酸插入的一个 DNA聚合酶,以协调修复“脏”或损坏的DNA末端,阻止BER。这些场景 在基因组不稳定性增加的时期变得特别具有生物学相关性(即,在 癌细胞和/或在治疗性处理期间)。本提案的总体目标是了解 每个BER组件单独的分子机制,并将这些活动在更大的BER 与受损的DNA修复中间体的共复合物。需要优雅的生物物理方法来阐明 这些BER的复杂性,并提供了一个基础,解释生物反应和 随后的治疗发展。我们处于推进这一科学前沿的独特地位 基于我在DNA损伤和修复方面的良好记录,组建了合作者团队, 多学科方法。为了实现这一目标,我们采用了一种综合的方法, 晶体学,中子晶体学,小角中子散射,分子动力学模拟, 酶动力学和单分子全内反射显微镜。使用这些方法,我们将 确定1)DNA损伤的位置如何在修复过程中改变DNA聚合酶机制; 2)如何 特征不佳的APE 1外切核酸酶反应过程是否损伤RNA和DNA修复块; 3) 质子在DNA损伤和修复过程中的机制作用是什么?4)DNA修复复合物如何 形成和组织结构?这组问题将从原子水平的机械理解 的关键BER组件的结构和动态的相互作用,在整个BER多蛋白质复合物。 通过这样做,我们将为解决建立细胞模型的固有挑战奠定基础, 开发针对DNA修复的新治疗方法。有了这些信息,我们将更接近 我们的长期目标是为合理的药物设计提供基础, 靶向参与DNA损伤的蛋白质的化学治疗剂和协同药物组合 反应

项目成果

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Bret D Freudenthal其他文献

Bret D Freudenthal的其他文献

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{{ truncateString('Bret D Freudenthal', 18)}}的其他基金

APE1 Cleavage Mechanisms during DNA Repair
DNA 修复过程中 APE1 切割机制
  • 批准号:
    10443576
  • 财政年份:
    2018
  • 资助金额:
    $ 38.25万
  • 项目类别:
Structural and Mechanistic Studies of DNA Repair
DNA修复的结构和机制研究
  • 批准号:
    9762147
  • 财政年份:
    2018
  • 资助金额:
    $ 38.25万
  • 项目类别:
APE1 Cleavage Mechanisms during DNA Repair
DNA 修复过程中 APE1 切割机制
  • 批准号:
    10202601
  • 财政年份:
    2018
  • 资助金额:
    $ 38.25万
  • 项目类别:
Structural and Mechanistic Studies of DNA Repair
DNA修复的结构和机制研究
  • 批准号:
    10622967
  • 财政年份:
    2018
  • 资助金额:
    $ 38.25万
  • 项目类别:
DNA Repair Strategies that Impact Genomic Stability During Oxidative Stress
氧化应激期间影响基因组稳定性的 DNA 修复策略
  • 批准号:
    9330157
  • 财政年份:
    2015
  • 资助金额:
    $ 38.25万
  • 项目类别:
DNA Repair Strategies that Impact Genomic Stability During Oxidative Stress
氧化应激期间影响基因组稳定性的 DNA 修复策略
  • 批准号:
    9136220
  • 财政年份:
    2015
  • 资助金额:
    $ 38.25万
  • 项目类别:
DNA Repair Strategies that Impact Genomic Stability During Oxidative Stress
氧化应激期间影响基因组稳定性的 DNA 修复策略
  • 批准号:
    9131846
  • 财政年份:
    2015
  • 资助金额:
    $ 38.25万
  • 项目类别:

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