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复制的机制及其与线粒体诱变和人类疾病的关系。将生物化学、结构生物学和分子遗传学的方法相结合，研究线粒体复制体的机制、结构和生理，重点是复制DNA解旋酶和线粒体单链DNA结合蛋白。结合我们和其他人对线粒体中的关键复制酶DNA聚合酶3的广泛研究，我们将先前的研究范围扩展到研究线粒体DNA复制叉处的蛋白质组装和功能，并探索体内和体外线粒体DNA复制的模式。 线粒体是动物体内产生能量的细胞器，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着重要作用，同样，线粒体功能障碍与人类疾病密切相关。线粒体功能障碍涉及广泛的神经系统疾病、代谢疾病、肌营养不良和肾病以及广泛的命名疾病。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，其导致线粒体和随后的细胞功能丧失。线粒体遗传病的流行和抗病毒和抗微生物药物的线粒体毒性的最近认识，迫切需要深入了解线粒体DNA复制装置的结构和功能。 公共卫生相关性：叙述：各种慢性、与年龄有关的疾病的一个共同特征是细胞产生能量的能力被破坏或干扰。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关键作用的细胞器，其功能障碍与许多病理学直接相关，包括那些在老龄化人口中最具代表性的病理学。因此，清楚地了解线粒体生物发生和能量产生以及这些过程在常见疾病状态下如何解除管制，对于有效（和经济地）治疗它们至关重要。