Coordinating Translesion DNA Synthesis Opposite Damaged DNA

协调跨损伤 DNA 合成与受损 DNA 相对

基本信息

批准号：
8401886
负责人：
ROBERT L EOFF
金额：
$ 23.46万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8401886
关键词：
Address Affect Affinity Age Aging Aging-Related Process Archaea Attention Base Excision Repairs Base Pairing Binding Biochemical Biochemistry Biologic Characteristic Biological Biological Assay Bypass Cell Culture Techniques Cell Cycle Cell Death Cell Line Cell Stress Process Cell division Cells Chemicals Chromosome Fragile Sites Code Colorectal Neoplasms Complex Crystallography DNA DNA Adducts DNA Damage DNA Fingerprinting DNA Modification Process DNA Structure DNA biosynthesis DNA lesion DNA-Directed DNA Polymerase Deuterium Development Disease Down-Regulation Enhancers Enzymes Epigenetic Process Equilibrium Event Evolution Exposure to Family Family member Functional disorder Funding Future G-Quartets G2 Phase Genetic Genetic Code Genetic Epistasis Genetic Materials Genome Genomic Instability Genomics Germ-Line Mutation Glioblastoma Glioma Goals Human Hydrogen Immunoglobulin Somatic Hypermutation Immunoprecipitation In Vitro Incidence Individual Instruction Ionizing radiation Kinetics Lead Length Lesion Life Link Maintenance Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mediating Methods Mind Modification Molecular Molecular Structure Mutagenesis Mutagens Mutation Nucleotides Organism Outcome Oxidative Stress Paraffin Embedding Pathologist Pathology Pathway interactions Patients Personal Satisfaction Phase Phenotype Phosphodiesterase I Phosphorylation Play Poison Polymerase Post-Translational Protein Processing Premature aging syndrome Process Prognostic Marker Prokaryotic Cells Property Proteins Proteomics Regulation Regulatory Element Research Resolution Role S Phase Signal Pathway Site Skin Cancer Slide Source Staging Stress Structure Substrate Specificity System Testing Thinking Tissues Tumor Biology UV induced DNA damage Ubiquitination Werner Syndrome X-Ray Crystallography base cancer therapy carcinogenesis deep sequencing design early onset helicase human WRN protein improved in vitro Assay in vivo insight laser capture microdissection loss of function mutation malignant breast neoplasm member molecular assembly/self assembly molecular dynamics neoplastic cell normal aging nucleotide metabolism prevent protein protein interaction repaired replication factor A research study response scaffold single molecule structural biology tumor tumor progression ultraviolet irradiation

项目摘要

Biological organisms are constantly required to prevent and/or repair damage to genomic DNA. Covalent modification ofthe genetic material is intimately related to processes that contribute to cellular dysfunction. Several mechanisms have evolved to prevent damage to DNA. Once the damage occurs the cell may respond with an arsenal of repair pathways that physically remove the lesions from the genome. If the modified portions of DNA are not removed prior to cell division then the machinery that copies the genetic material, the replisome, will encounter the damage, which often proves inhibitory to accurate DNA replication events. Central to the replisome is an enzyme called a DNA polymerase. The actions of these enzymes play an important role in determining whether a lesion bypass event is accurate or mutagenic. There are several types of DNA polymerase in every cell across the spectrum of life. Some DNA polymerases have been retained throughout evolution because they are an extremely accurate and focused means of synthesizing Watson-Crick base pairs. These so-called replicative DNA polymerases are often less able to bypass DNA adducts. Other specialized polymerases possess lesion bypass abilities that can aid the replication fork when it encounters damage, but how these two types of DNA polymerases are coordinated in response to DNA damage remains unclear. Structural approaches including x-ray crystallography and hydrogen-deuterium exchange mass spectrometry will be combined with functional kinetic analysis and cellular studies in an effort to determine how specialized DNA polymerases interact with the Werner syndrome protein during bypass of damaged DNA. Werner syndrome is characterized by premature aging and genomic instability. Understanding how the enzymes that copy our genome function when they encounter DNA damage is an important part of understandig why certain chemicals are toxic, how cancer develops, and even relates to why we age. The goals of our research seek to answer questions related to how different types of "DNA making" enzymes function to maintain the integrity of our genetic material.

不断需要生物生物体来预防和/或修复对基因组DNA的损害。共价遗传物质的修饰与导致细胞功能障碍的过程密切相关。几种机制已经进化以防止DNA损坏。一旦损坏发生，细胞可能用修复途径的武库反应，从物理上清除基因组病变。如果是在细胞分裂之前未删除DNA的修改部分材料（重新质体）会遇到损坏，通常证明抑制精确的DNA复制事件。重置体的中心是一种称为DNA聚合酶的酶。这些酶发挥的作用确定病变旁路事件是准确还是诱变的重要作用。整个生命范围的每个细胞中，每个细胞中都有几种类型的DNA聚合酶。一些DNA 聚合酶在整个演化过程中都保留了，因为它们是非常准确且专注的综合沃森 - 克里克底座对的手段。这些所谓的复制性DNA聚合酶通常较少能够绕过DNA加合物。其他专业聚合酶具有病变旁路能力，可以帮助复制叉会遇到损害时，但是这两种类型的DNA聚合酶如何协调对DNA损伤的反应尚不清楚。结构方法，包括X射线晶体学和氢 - 居民交换质谱法将与功能动力学分析和细胞研究是为了确定专门的DNA聚合酶如何与Werner相互作用 DNA受损旁路期间综合征蛋白。 Werner综合征的特征是过早衰老和基因组不稳定性。了解当它们复制基因组功能时如何功能遇到DNA损伤是了解某些化学物质有毒的重要组成部分发展，甚至与我们变老的原因有关。我们研究的目标旨在回答与不同类型的“ DNA制造”酶如何保持遗传物质的完整性。