Mitochondrial DNA Replisome: Mechanism, Structure and Physiology

线粒体 DNA 复制体：机制、结构和生理学

• 批准号: 8061977
• 负责人: LAURIE SIMON KAGUNI
• 金额: $ 33.43万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061977
• 关键词: Animals; Antiviral Agents; Biochemical; Biochemistry; Biogenesis; Cell physiology; Cells; Chronic; DNA biosynthesis; DNA replication fork; DNA-Directed DNA Polymerase; Defect; Development; Disease; Enzymes; Escherichia coli; Functional disorder; Funding; Future; Health; Hereditary Disease; Human; In Vitro; Kidney Diseases; Lead; Link; Metabolic Diseases; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Molecular Genetics; Muscular Dystrophies; Mutagenesis; N-terminal; Names; Nuclear; Organelles; Pathology; Physical assessment; Physiological; Physiology; Play; Prevalence; Process; Production; Property; Proteins; Research; Role; SS DNA BP; Site; Specificity; Structure; Syndrome; Tissues; Toxic effect; Work; abstracting; age related; aging population; antimicrobial drug; base; helicase; human disease; in vivo; insight; mitochondrial DNA mutation; mitochondrial dysfunction; nervous system disorder; protein function; protein protein interaction; public health relevance; recombinational repair; replication factor A; structural biology

DESCRIPTION (provided by applicant): Abstract: The long-term objective of the proposed work is the elucidation of the mechanism of DNA replication in animal mitochondria, and its relationship to mitochondrial mutagenesis and human disease. A combined approach of current methods in biochemistry, structural biology and molecular genetics will be pursued to study the mechanism, structure and physiology of the mitochondrial replisome, with a focus on the replicative DNA helicase and the mitochondrial single-stranded DNA-binding protein. In combination with the extensive studies by us and others on the key replicative enzyme in mitochondria, DNA polymerase 3, we expand the scope of prior research to study the assembly and function of proteins at the mitochondrial DNA replication fork, and to probe the modes of mitochondrial DNA replication in vivo and in vitro. Mitochondria are the energy-producing organelle in animals and mitochondrial function impacts nearly every aspect of cellular function. Thus, mitochondria play a major role in human health and likewise, mitochondrial dysfunction is intricately associated with human disease. Mitochondrial dysfunction is implicated in a wide range of neurological diseases, in metabolic diseases, in muscular dystrophies and nephropathies, and in a broad spectrum of named disorders. Defects in mitochondrial biogenesis lead to mitochondrial DNA mutation, depletion and deletion syndromes that result in loss of mitochondrial and subsequent cellular function. The prevalence of mitochondrial genetic disease and recent recognition of the mitochondrial toxicity of antiviral and antimicrobial drugs the critical need for an in-depth understanding of the structure and functions of the mitochondrial DNA replication apparatus. PUBLIC HEALTH RELEVANCE: Narrative: A common feature in diverse chronic, age-related diseases is a breakdown or disturbance in the cell's ability to produce energy. Central to the cellular energy production is the mitochondrion, an organelle that plays a crucial role in multiple metabolic processes, and whose dysfunction is linked directly to many pathologies, including those most represented in an aging population. Therefore, a clear understanding of mitochondrial biogenesis and energy production and how these processes are deregulated in common disease states, is essential to treating them effectively (and economically).

描述（由申请人提供）：摘要：拟议工作的长期目标是阐明动物线粒体中DNA复制机制及其与线粒体诱变和人类疾病的关系。当前方法在生物化学，结构生物学和分子遗传学方面的一种组合方法将被追求研究线粒体再生体的机制，结构和生理学，重点侧重于复制性DNA解旋酶和线粒体单一型单链DNA结合蛋白。结合我们和其他人对线粒体中的关键复制酶的广泛研究，DNA聚合酶3，我们扩大了先前研究的范围，以研究蛋白质在线粒体DNA复制叉上蛋白质的组装和功能，并探测Mitochondirial DNA在Vivo InViv和Vitro的模式。 线粒体是动物中产生能量的细胞器，线粒体功能几乎影响细胞功能的各个方面。因此，线粒体在人类健康中起主要作用，同样，线粒体功能障碍与人类疾病无关。线粒体功能障碍与多种神经疾病，代谢疾病，肌肉营养不良和肾病以及广泛的命名疾病有关。线粒体生物发生的缺陷导致线粒体DNA突变，耗竭和缺失综合征导致线粒体和随后的细胞功能丧失。线粒体遗传疾病的患病率以及对抗病毒和抗菌药物线粒体毒性的最新认识，对线粒体DNA复制的结构和功能的关键需求的迫切需要。 公共卫生相关性：叙事：多种慢性，与年龄相关的疾病的共同特征是细胞产生能量能力的分解或干扰。细胞能量产生的核心是线粒体，这是一种在多种代谢过程中起着至关重要的作用的细胞体，其功能障碍直接与许多病理联系在一起，包括在老龄化人群中最大的病理。因此，对线粒体生物发生和能量产生以及在普通疾病状态下如何消除这些过程的清晰了解对于有效（经济上）对待它们至关重要。