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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

基本信息

批准号：
10796464
负责人：
Elise Fouquerel
金额：
$ 6.33万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10796464
关键词：
Air Pollution Antioxidants Award Base Excision Repairs Centromere Chromosomal Breaks Chromosomal Instability 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 Knowledge Lesion Link Malignant Neoplasms Mediating Mutation Oxidative Stress Parents Pathway interactions Phenotype Play Poly(ADP-ribose) Polymerase Inhibitor Poly(ADP-ribose) Polymerases Post-Translational Protein Processing Production Proteins Reactive Oxygen Species Rest Role Source Therapeutic Ultraviolet Rays Work base cancer therapy 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

项目摘要

Mechanistic insight into oxidative stress-mediated genomic instability Parent award: R35GM142982 ABSTRACT Genome instability is characterized by genetic alterations that include DNA base mutations, chromosome breaks, rearrangements and instability, hallmarks of various human diseases including cancer. Chromosome instability (CIN) that results from inaccurate chromosomal segregation, originates from telomere and centromere dysfunctions. 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. To this end, we are leveraging 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 aim to 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, an 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见解家长奖：R35GM142982 抽象的基因组不稳定的特征是遗传改变，包括 DNA 碱基突变、染色体断裂、重排和不稳定是包括癌症在内的各种人类疾病的特征。染色体不稳定 (CIN) 由不准确的染色体分离引起，起源于端粒和着丝粒功能障碍。大量流行病学研究强调了氧化应激暴露在疾病中的核心作用。端粒和着丝粒功能障碍的发生。然而，至关重要的是，其背后的机制功能障碍尚不清楚。氧化应激是由于氧化应激产生的不平衡造成的活性氧和细胞抗氧化防御。它既有内源性的来源，也有外源性的来源。环境来源（线粒体代谢、紫外线、空气污染、香烟烟雾）。它的无处不在凸显正确理解其对人类健康影响的重要性。氧化应激的一个主要影响是诱导氧化 DNA 损伤，通过碱基切除修复 (BER) 途径进行修复，其中聚（ADP-核糖）聚合酶（PARP）是主要参与者。 PARP1 和 PARP2 负责聚（ADP- 核糖基化，蛋白质的翻译后修饰，调节其招募和相互作用蛋白质靶标。该提案的目标是（i）揭示氧化应激介导的机制基因组不稳定性，重点关注其对端粒和着丝粒的影响，这两个基因座对基因组至关重要 (ii) 破译 PARP 酶在保护端粒和着丝粒 DNA 方面的贡献 DNA 氧化损伤时。为此，我们正在利用一种独特且创新的化学光遗传学工具在端粒和着丝粒处局部诱导氧化 DNA 损伤，而不影响其余部分基因组。这将使我们能够明确地将表型变化和 PARP 依赖机制与端粒或着丝粒损伤。这些项目旨在填补关于聚（ADP- 核糖基化在基因组的两个关键区域协调 DNA 修复。他们还将阐明如何氧化应激是基因组不稳定的普遍因素，可导致多种人类疾病。最终，我们的工作将有助于开发针对基因组特定区域的新型治疗策略并为已广泛用于癌症治疗的 PARP 抑制剂的合理设计和使用提供信息。