Oxidative DNA Damage And Its Processing

DNA氧化损伤及其处理

• 批准号: 7964026
• 负责人: Vilhelm Bohr
• 金额: $ 57.29万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964026
• 关键词: Aging; Aging-Related Process; Base Excision Repairs; Cells; DNA; DNA Modification Process; DNA Repair; DNA lesion; Development; Excision; Functional disorder; Genetic Recombination; Genome; Genomic Instability; Goals; Individual; Lead; Lesion; Life; Lipids; Malignant Neoplasms; Metabolism; Mitochondrial DNA; Modeling; Modification; Mutagenesis; Mutate; Nuclear; OGG1 gene; Organism; Oxidative Stress; Pathway interactions; Play; Premature aging syndrome; Process; Property; Proteins; Repair Complex; Role; Site; Stem cells; base; environmental agent; human embryonic stem cell; in vivo; interest; oxidative DNA damage; protein protein interaction; repair enzyme; repaired; response

Oxidative lesions are removed from DNA primarily via the base excision repair (BER) pathway. BER is carried out through four enzymatic steps, but it is now clear that several other proteins modulate BER efficiency through protein-protein interactions. We and others identified several protein interactions for the core BER enzymes. These protein interactions are physical and functional and together support the "passing of baton" model, in which BER takes place in different steps supported by individual protein interactions that are components of a repair complex, possibly situated at the DNA lesion. We are studying other protein interactions of OGG1 in order to understand how repair of oxidative lesions is regulated in vivo. We find that OGG1 also interacts with the recombination protein RAD52, suggesting a possible interplay between these two repair pathways. We find a reciprocal functional interaction between these two proteins, in which RAD52 stimulates OGG1 catalytic activity and OGG1 inhibits RAD52-catalysed DNA strand annealing and invasion. Moreover, the physical interaction between OGG1 and RAD52 increases in cells exposed to oxidative stress, indicating that this interaction is important in the cellular response to oxidative DNA damage. Since stem cells are critically important in development, it is very important to understand how these cells maintain their genome. We have therefore examined DNA repair properties in human embryonic stem cells. Interestingly, these cells have upregulated DNA repair and one of the pathways that is markedly upregulated is the base excision repair pathway for removal of oxidative DNA damage. This testifies to the central importance of this pathway in development.

氧化损伤主要通过碱基切除修复（BER）途径从DNA中去除。BER是通过四个酶的步骤进行的，但现在很清楚，其他几种蛋白质通过蛋白质之间的相互作用调节BER的效率。我们和其他人确定了核心BER酶的几种蛋白质相互作用。这些蛋白质相互作用是物理的和功能性的，并共同支持“接力棒传递”模型，在该模型中，BER发生在不同的步骤中，由单个蛋白质相互作用支持，这些相互作用是修复复合体的组成部分，可能位于DNA损伤处。我们正在研究OGG1的其他蛋白质相互作用，以了解氧化损伤的修复是如何在体内调节的。我们发现OGG1也与重组蛋白RAD52相互作用，这表明这两种修复途径之间可能存在相互作用。我们发现这两个蛋白之间存在互反的功能相互作用，其中RAD52刺激OGG1的催化活性，而OGG1抑制RAD52催化的DNA链退火和入侵。此外，暴露于氧化应激的细胞中，OGG1和RAD52之间的物理相互作用增加，表明这种相互作用在细胞对氧化DNA损伤的反应中很重要。