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Roles of Lig3 and XRCC1 Genes in Genome Stability

Lig3 和 XRCC1 基因在基因组稳定性中的作用

基本信息

批准号：
10660387
负责人：
Alan E Tomkinson
金额：
$ 33.77万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-20 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660387
关键词：
Adenine Aging Base Excision Repairs Binding CASP1 gene Carrier Proteins Cell Death Cell Survival Cells Cellular Stress Complex Cytoplasm Cytosine DNA DNA Damage DNA Ligases DNA Repair Enzymes DNA Repair Inhibition DNA glycosylase DNA lesion DNA metabolism Data Development Electron Transport Energy Metabolism Excision Exposure to Functional disorder Generations Genes Genetic Transcription Genome Genome Stability Guanine Health Human Hydrogen Peroxide Inflammasome Inflammation Inflammatory Innate Immune Response Lesion Ligase Link Maintenance Malignant Neoplasms Mediating Metabolic Diseases Metabolism Mitochondria Mitochondrial DNA Mitochondrial Electron Transport Complex I Mitochondrial Proteins Mutation NADH dehydrogenase (ubiquinone)Nerve Degeneration Neurodegenerative Disorders Non-Malignant Nuclear Nucleic Acids OGG1 gene Organelles Oxidative Phosphorylation Oxidative Stress Pathologic Pathway interactions Play Poly(ADP-ribose) Polymerase Inhibitor Predisposition Process Production Protein Biosynthesis Proteins RARRES3 gene Reactive Oxygen Species Reagent Regulation Role Site Stimulator of Interferon Genes Superoxides Testing Therapeutic Work XRCC1 gene base cancer cell cell growth regulation design environmental agent free radical oxygen human disease improved inhibitor insight interest macromolecule mitochondrial dysfunction mitochondrial genome novel novel therapeutic intervention oxidative DNA damage oxidative damage prevent refractory cancer repaired therapeutic target therapy resistant tool

项目摘要

ABSTRACT While the ATP production by oxidative phosphorylation in mitochondria provides the energy for the synthesis of proteins, nucleic acids and other macromolecules, this process generates as a by-product reactive oxygen species that present a unique challenge for the circular mitochondrial genome. Notably, the accumulation of oxidative DNA damage in mitochondrial DNA inhibits the transcription of key electron transport proteins encoded by the mitochondrial genome disrupting electron transport leading to a further increase in reactive oxygen species. In addition to the reactive oxygen species generated within mitochondria, some environmental DNA damaging agents preferentially cause damage in the mitochondrial genome compared with the nuclear genome. Interestingly, although the oxidized base 8-oxoguanine is repaired, oxidative DNA damage also induces degradation of the mitochondrial genome. Since there are multiple copies of the mitochondrial genome per organelle, it has been suggested that the removal of damaged genomes by degradation serves to prevent mutations. For oxidative DNA damage, it is not known what lesion(s) triggers genome degradation and whether this reduces mutations. In Specific Aim 1, we will test the hypothesis that the MUTYH DNA glycosylase protects the mitochondrial genome from mutation by stably binding to genomes with the 8-oxoG:adenine mispairs or the 8-oxoG:abasic site repair intermediate and targeting them for degradation using unique tools and reagents developed by the PI and co-I. The proposed studies will elucidate the mechanisms that engage with oxidative DNA damage in mitochondria to either repair the damage or target the damaged genome for degradation. Specific Aim 2 builds upon a novel interaction identified between the mitochondrial DNA ligase, DNA ligase IIIa (LigIIIa) , and NDUFAB1, an accessory subunit of complex I of the electron transport chain that provides possible explanation as to why the LigIIIa inhibitor rapidly induces production of mitochondrial superoxide. We will characterize the interaction between mitochondrial LigIIIa and complex I to determine whether LigIIIa has a non-canonical role in complex I function, thereby linking mitochondrial DNA metabolism with oxidative phosphorylation. Cancer and non-malignant cells respond very differently to the dysfunction caused by inhibition of mitochondrial LigIIIa with cancer cells activating an inflammatory cell death pathway whereas non-malignant cells activate mitophagy and pro-inflammatory cell stress pathways. In Specific Aim 3, we will delineate the mechanisms and regulation of the cellular pathways that respond to mitochondrial dysfunction induced by inhibition of mitochondrial LigIIIa in cancer and non-malignant cells. Alterations in mitochondrial function that are usually associated with increased oxidative stress have been identified as the causative factor in certain human metabolic and neurodegenerative diseases and implicated in inflammation, cancer and ageing. Thus, our proposed studies will provide fundamental insights as to how mitochondria maintain their genome and suggest how mitochondrial dysfunction can be mitigated or exploited to improve human health.

摘要线粒体中氧化磷酸化产生的ATP为合成ATP提供能量，蛋白质，核酸和其他大分子，这一过程产生的副产品活性氧这些物种对环形线粒体基因组提出了独特的挑战。值得注意的是，线粒体DNA的氧化损伤抑制了关键的电子传递蛋白的转录，线粒体基因组破坏电子传递导致活性氧进一步增加物种除了线粒体内产生的活性氧外，与核基因组相比，损伤剂优先在线粒体基因组中引起损伤。有趣的是，虽然氧化的碱基8-氧代鸟嘌呤被修复，但氧化DNA损伤也诱导了DNA损伤。线粒体基因组的降解。由于每个人都有多个线粒体基因组拷贝，细胞器，有人认为，通过降解去除受损的基因组有助于防止突变。对于氧化性DNA损伤，尚不清楚是什么损伤触发了基因组降解，以及这减少了突变。在具体目标1中，我们将测试MUTYH DNA糖基化酶保护线粒体基因组通过稳定结合到具有8-oxoG：腺嘌呤错配的基因组或具有8-oxoG：腺嘌呤错配的基因组而突变。 8-oxoG：脱碱基位点修复中间体，并使用独特的工具和试剂靶向它们进行降解由PI和co-I开发。拟议的研究将阐明参与氧化的机制线粒体中的DNA损伤，以修复损伤或靶向受损的基因组进行降解。特异性目的2建立在线粒体DNA连接酶、DNA连接酶和DNA连接酶之间的一种新的相互作用的基础上。 IIIa（LigIIIa）和NDUFAB 1，NDUFAB 1是电子传递链的复合物I的辅助亚基，其提供可能的解释，为什么LigIIIa抑制剂迅速诱导线粒体超氧化物的生产。我们将表征线粒体LigIIIa和复合物I之间的相互作用，以确定LigIIIa是否具有在复合物I功能中的非典型作用，从而将线粒体DNA代谢与氧化磷酸化癌细胞和非恶性细胞对抑制引起的功能障碍的反应非常不同线粒体LigIIIa与癌细胞激活炎性细胞死亡途径，而非恶性细胞激活线粒体自噬和促炎细胞应激途径。在具体目标3中，我们将描述机制和调节的细胞途径，响应线粒体功能障碍诱导的抑制癌细胞和非恶性细胞中的线粒体LigIIIa。线粒体功能的改变，通常与增加的氧化应激有关的氧化应激已被确定为某些人中的致病因素代谢和神经退行性疾病，并与炎症、癌症和衰老有关。所以我们拟议中的研究将提供关于线粒体如何维持其基因组的基本见解，并建议如何缓解或利用线粒体功能障碍来改善人类健康。