Replication Fork Repair

复制叉修复

• 批准号: 10696070
• 负责人: SUSAN THOMAS LOVETT
• 金额: $ 50.46万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696070
• 关键词: Address; Affect; Aging; Antibiotic Resistance; Bacteria; Bacteria sigma factor KatF protein; Base Pairing; Binding; Binding Proteins; Biochemical; Cell Survival; Cells; Closure by clamp; Complex; Copying Processes; DNA; DNA Damage; DNA Polymerase III; DNA Repair; DNA biosynthesis; DNA metabolism; DNA replication fork; DNA-Directed RNA Polymerase; Defect; Development; Electron Transport Complex III; Escherichia coli; Event; Evolution; Genes; Genetic; Genetic Diseases; Genetic Materials; Genetic Transcription; Genome; Genome Stability; Genomic DNA; Genomic Instability; Goals; Gram-Negative Bacteria; Growth; Head; Holoenzymes; Human; Immunologics; Infection; Information Protection; Interruption; Left; Malignant Neoplasms; Mediating; Microscopic; Molecular Biology; Mutation; Neurologic; Nucleotides; Organism; Pathway interactions; Physiology; Play; Premature aging syndrome; Process; Production; Proliferating; Property; Protein Biochemistry; Proteins; RNA; Reaction; Regulatory Pathway; Ribosomal RNA; Role; Signal Transduction; Site; Starvation; Structure; System; Testing; Toxin; Transcript; Transcription Coactivator; Transcriptional Regulation; Virulence Factors; Visualization; Work; cold shock protein; conflict resolution; genetic analysis; genetic approach; helicase; infectious disease treatment; inhibitor; interest; microbial; microorganism; model organism; mutant; novel; pathogenic bacteria; pathogenic microbe; prevent; protein complex; rRNA Operon; recruit; repaired; response; rho; transcription termination

Project Summary Replication fork repair is essential for cell survival and stability of genetic material. In humans, inefficiency of repair is associated with cancer proneness, neurological, immunological, developmental defects and premature aging. For microbial pathogens, the ability to repair DNA damage is required for survival of bacterial pathogens and promotes genetic change that can contribute to antibiotic resistance and persistence of infection. The long-term goal of our studies is a more complete mechanistic understanding of the repair of replication forks and how it affects genomic stability. This will be accomplished using the genetic system of Escherichia coli, whose physiology is well understood. A central interest is how bacterial cells signal difficulties in replication to facilitate repair and how this is integrated with other aspects of bacterial growth. By biochemical and genetic analysis, this work will elucidate how a newly discovered conserved DNA helicase protein, YoaA, interacts with the replisome to overcome barriers in replication. This study will specifically address the influence of RNA transcription and DNA protein complexes on replication and genomic instability and what mechanisms are used to overcome conflicts between replication and transcription machinery. The regulatory pathway controlled by stringent starvation protein, SspA, will also be explored to discover how it impacts DNA metabolism. Because all cells repair DNA in fundamentally similar ways by evolutionarily related pathways, these studies using microbial model organisms should reveal mechanisms applicable to repair of DNA in human cells. In addition, because the DNA damage response in microbial pathogens plays a role in toxin production, antibiotic resistance and persistence of infection, this work could provide new information important for the treatment of infectious disease.

项目概要 复制叉修复对于细胞存活和遗传物质的稳定性至关重要。在人类中， 修复效率低下与癌症倾向、神经学、免疫学、 发育缺陷和过早衰老。对于微生物病原体来说，修复DNA的能力 损伤是细菌病原体生存所必需的，并促进基因变化，从而可以 导致抗生素耐药性和感染持续存在。 我们研究的长期目标是对修复的更完整的机制了解 复制叉及其如何影响基因组稳定性。这将通过遗传来完成 大肠杆菌的系统，其生理学已广为人知。一个中心兴趣是如何 细菌细胞发出复制困难信号以促进修复，以及如何将其与 细菌生长的其他方面。通过生化和遗传分析，这项工作将阐明 新发现的保守 DNA 解旋酶蛋白 YoaA 如何与复制体相互作用 克服复制中的障碍。这项研究将专门解决 RNA 的影响 转录和 DNA 蛋白复合物对复制和基因组不稳定性的影响 机制用于克服复制和转录机制之间的冲突。 还将探索由严格饥饿蛋白 SspA 控制的调控途径 了解它如何影响 DNA 代谢。 因为所有细胞都通过进化相关的途径以基本相似的方式修复 DNA， 这些使用微生物模型生物体的研究应该揭示适用于修复的机制 人类细胞中的DNA。此外，由于微生物病原体的DNA损伤反应 在毒素产生、抗生素耐药性和持续感染中发挥作用，这项工作可以 为传染病的治疗提供重要的新信息。