Mechanistic insight into oxidative stress-mediated genome instability

氧化应激介导的基因组不稳定性的机制见解

• 批准号: 10663882
• 负责人: Elise Fouquerel
• 金额: $ 37.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663882
• 关键词: Air Pollution; Antioxidants; Base Excision Repairs; Centromere; Chromosomal Instability; Chromosomes; Chronic; DNA; DNA Damage; DNA Repair; DNA Repair Gene; Data; Development; Enzymes; Excision Repair; Exposure to; Functional disorder; Genome; Genome Stability; Genomic Instability; Goals; Health; Human; Inherited; Knowledge; Lesion; Link; Malignant Neoplasms; Mediating; Mutation; Oxidative Stress; Pathway interactions; Phenotype; Play; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Post-Translational Protein Processing; Premature aging syndrome; Production; Proteins; Reactive Oxygen Species; Rest; Role; Single Strand Break Repair; Source; Therapeutic; Ultraviolet Rays; Work; base; cancer therapy; cancer type; cigarette smoke; design; epidemiology study; genomic locus; human disease; innovation; insight; mitochondrial metabolism; novel; novel therapeutic intervention; oxidative DNA damage; rational design; recruit; segregation; telomere; tool; treatment strategy

Mechanistic insight into oxidative stress-mediated genome instability Summary: Genome instability is characterized by genetic alterations ranging from DNA base mutations to chromosome rearrangements that are drivers of many inherited human diseases, various types of cancer and premature ageing. Chromosome instability, especially, results from inaccurate chromosomal segregation caused by telomere and centromere dysfunction. Numerous epidemiologic studies have highlighted the central role of oxidative stress exposures in the occurrence of telomere and centromere dysfunction. Critically, however, the mechanisms underlying the dysfunction are not clearly understood. Oxidative stress results from an imbalance between the production of reactive oxygen species and cellular antioxidant defenses. It arises from endogenous sources as well as from environmental sources (mitochondria metabolism, UV light, air pollution, cigarette smoke). Its ubiquity highlights the importance of properly understanding its impacts on human health. A major impact of oxidative stress is the induction of oxidative DNA damage that are repaired by the base excision repair (BER) pathway in which poly(ADP-ribose) polymerases (PARPs) are major actors. PARP1 and PARP2 are responsible for the poly(ADP-ribosyl)ation, a post-translational modification of proteins that modulates the recruitment and interactions of their protein targets. The goals of this proposal are to (i) uncover the mechanisms of oxidative stress-mediated genome instability with a focus on its impact on telomeres and centromeres, two genomic loci crucial for genome stability and (ii) decipher the contribution of PARP enzymes in the protection of telomeric and centromeric DNA upon oxidative DNA damage. More specifically, we aim to evaluate the impact of chronic induction of oxidized DNA bases and BER single strand break intermediates on centromere and telomere integrity. We will also identify and assess the impact of poly(ADP-ribosyl)ation on centromeric and telomeric protein targets. To this end, we will leverage a unique and innovative chemoptogenetic tool that induces oxidative DNA damage locally at telomeres and at centromeres without impacting the rest of the genome. This will allow us to unequivocally link phenotypic changes and PARP dependent mechanisms to the telomeric or centromeric lesions. These projects will fill a long-standing gap of knowledge on how poly(ADP-ribosyl)ation orchestrates DNA repair at two crucial regions of the genome. They will also shed light on how oxidative stress, a ubiquitous factor of genome instability, can drive numerous human diseases. Ultimately, our work will contribute to the development of novel therapeutic strategies targeting specific regions of the genome and inform the rational design and use of the PARP inhibitors already widely used in cancer treatments.

氧化应激介导的基因组不稳定性的机制洞察 摘要： 基因组不稳定的特征是从dna碱基突变到染色体的遗传改变。 重组是许多人类遗传性疾病、各种癌症和早产儿的驱动因素 老龄化。染色体不稳定，特别是由于不准确的染色体分离引起的 端粒和着丝粒功能障碍。许多流行病学研究强调了艾滋病的核心作用。 氧化应激暴露在端粒和着丝粒功能障碍的发生中。然而，关键的是， 这种功能障碍的潜在机制尚不清楚。氧化应激是由失衡引起的 活性氧的产生和细胞的抗氧化防御之间的关系。它是由内源性的 来源以及环境来源(线粒体新陈代谢、紫外线、空气污染、香烟 烟)。它的普遍存在突显了正确理解其对人类健康影响的重要性。一位少校 氧化应激的影响是诱导通过碱基切除修复修复的氧化DNA损伤 (BER)途径，其中聚(ADP-核糖)聚合酶(PARP)是主要参与者。PARP1和PARP2是 负责多聚(ADP-核糖基)修饰，这是一种蛋白质的翻译后修饰，调节 它们的蛋白质靶标的招募和相互作用。这项提议的目标是：(一)揭示 氧化应激介导的基因组不稳定，重点是它对端粒和着丝粒的影响，两 对基因组稳定性至关重要的基因组基因座和(Ii)破译PARP酶在保护 DNA氧化损伤时的端粒和着丝粒DNA。更具体地说，我们的目标是评估影响 在着丝粒和着丝粒上慢性诱导DNA氧化碱基和BER单链断裂中间体 端粒完整性。我们还将确定和评估聚(ADP-核糖)对着丝粒和着丝粒的影响。 端粒蛋白靶标。为此，我们将利用一种独特而创新的化学光遗传工具来诱导 DNA氧化损伤位于端粒和着丝粒的局部，而不影响基因组的其余部分。这 将允许我们明确地将表型变化和PARP依赖机制与端粒或 着丝粒病变。这些项目将填补长期以来关于聚(ADP-核糖基)如何发生核糖化的知识空白 在基因组的两个关键区域协调DNA修复。他们还将阐明氧化应激是如何， 基因组不稳定是一种普遍存在的因素，可以导致许多人类疾病。最终，我们的工作将 帮助开发针对基因组特定区域的新治疗策略并提供信息 已广泛应用于癌症治疗的PARP抑制剂的合理设计和使用。