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Dissecting dual function of Pol gamma in mtDNA replication and oxidative damage r

解析 Pol gamma 在 mtDNA 复制和氧化损伤中的双重功能

基本信息

批准号：
9352354
负责人：
Yuhui Yin
金额：
$ 29.2万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352354
关键词：
Adopted Apoptosis Base Excision Repairs Biochemical Biophysics Cardiovascular Diseases Cardiovascular system Cell division Cells Complex Crystallization Cytosine DNA DNA Damage DNA Modification Process DNA Repair DNA Repair Pathway DNA biosynthesis DNA polymerase gamma DNA-(apurinic or apyrimidinic site) lyase Data Development Energy Supply Environmental Risk Factor Enzyme Kinetics Enzymes Excision Excision Repair Exhibits Exonuclease Foundations Goals Grant Guanine Health Human Huntington Disease Knowledge Lesion Ligase Malignant Neoplasms Mitochondria Mitochondrial DNA Molecular Conformation Mutation Myopathy Neurodegenerative Disorders Nuclear Nucleotides Organelles Oxidative Phosphorylation Oxides Parkinson Disease Pathway interactions Polymerase Premature aging syndrome Process Radiation Reaction Reactive Oxygen Species Repair Complex Role Set protein Single Strand Break Repair Structure Testing base chemical synthesis combat comparative enzyme activity helicase in vivo knockout gene mitochondrial dysfunction nervous system disorder nuclease oxidation oxidative DNA damage oxidative damage prevent public health relevance repaired replicase skeletal structural biology

项目摘要

DESCRIPTION (provided by applicant): Integrity of mitochondrial DNA is vital to functions of the organelle that include supply energy to sustain cellular activities, cell division and programmed cell death. Mutations on mitochondrial DNA are associated with neurodegenerative disorders, such as Parkinson's and Huntington's diseases, cardiovascular and skeletal muscular disorders. The high concentration of reactive oxygen species in mitochondria causes abundant oxidative damage on DNA. DNA damage repair is chiefly repaired by the base excision repair pathway. Although a wealth of knowledge on nuclear DNA base excision repair exists, comparatively much less is known about mitochondrial DNA repair. We propose to study the structures and functions of a central component in human mitochondrial DNA repair pathway, DNA polymerase gamma (Pol ?), and its interaction with another critical component, mitochondrial exonuclease ExoG. The proposed studies combine structural biology, solution biophysics, enzyme kinetics as well as chemical synthesis aiming to provide a comprehensive view of mitochondrial base excision repair.

描述（由申请人提供）：线粒体DNA的完整性对细胞器的功能至关重要，包括提供能量以维持细胞活动、细胞分裂和程序性细胞死亡。线粒体DNA上的突变与神经退行性疾病有关，如帕金森病和亨廷顿病、心血管疾病和骨骼肌疾病。线粒体内高浓度的活性氧对DNA造成大量的氧化损伤。DNA损伤修复主要通过碱基切除修复途径进行。虽然核DNA碱基切除修复存在丰富的知识，相对少得多的线粒体DNA修复所知。我们打算研究人线粒体DNA修复途径中的一个核心组分DNA聚合酶γ（Pol？）的结构和功能，以及它与另一个关键组分线粒体核酸外切酶ExoG的相互作用。拟议的研究结合联合收割机结构生物学，溶液生物物理学，酶动力学以及化学合成，旨在提供线粒体碱基切除修复的全面视图。