Control of elongation of DNA replication

DNA 复制延伸的控制

• 批准号: 8068266
• 负责人: Jue D. Wang
• 金额: $ 26.19万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8068266
• 关键词: Affect; Amino Acids; Antibiotic Resistance; Bacillus subtilis; Bacteria; Cell Death; Cell physiology; Cells; Complex; DNA; DNA Sequence Rearrangement; DNA biosynthesis; Defect; Development; Disease; Environment; Escherichia coli; Event; Fluorescence Microscopy; Generations; Genome; Genomic Instability; Genomics; Goals; Gram-Positive Bacteria; Guanosine; Health; Human; Knowledge; Malignant Neoplasms; Mediating; Metabolic Control; Molecular; Molecular Profiling; Monitor; Mutagenesis; Mutation; Nature; Nucleotides; Nutrient; Organism; Pathway interactions; Pentas; Play; Prevalence; Preventive; Regulation; Role; Starvation; Stress; Techniques; Testing; Transcriptional Regulation; genome-wide; in vivo; microbial; novel; prevent; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Accurate and complete DNA replication is of paramount importance for all organisms. Replication elongation is highly susceptible to disruptions leading to fateful consequences including incomplete replication, mutations and genome rearrangements, which can underlie cell death, genomic disorders, tumor formation and progression. Despite the importance of minimizing disruption of DNA replication elongation, how cells manage to do so remains poorly understood. We recently employed genome-wide, systematic approaches to identify a novel nutrient-responsive regulation of replication elongation in the Gram-positive bacterium Bacillus subtilis. We propose that this regulation keeps replication elongation under metabolic control to prevent disruption of replication, and together with mechanisms that rescue and reactivate the disrupted replication forks, maintains genome integrity robustly. Such mechanisms are likely to exist in other organisms and play far more important roles than previously conceived. We aim to evaluate the role of regulation of replication elongation, its prevalence in other bacteria such as E. coli, and to define the molecular differences between regulated replication arrests and disruptive replication arrests. Our study will contribute significantly to knowledge of the connection between the replication elongation complex and its cellular environment. This will deepen the understanding of the possible roles of uncontrolled replication in tumorigenesis and genomic disorders and elucidate fundamental principles underlying genome integrity. The specific aims are: 1. Examine the role of a novel regulatory mechanism of replication elongation in B. subtilis; 2. Characterize key events at replication forks following diverse replication arrests; 3. Characterize the control of replication elongation in E. coli. PUBLIC HEALTH RELEVANCE: We discovered a new way that bacteria control duplication of their DNA. Investigating this pathway elucidates novel and conserved principles of control of DNA duplication. Loss of this control potentially leads to genome rearrangements and mutagenesis, which underlies several human genomic disorders and cancers. Understand this pathway is also important for understanding microbial development of antibiotic resistance.

描述(由申请人提供)：准确和完整的DNA复制对所有生物体都是至关重要的。复制延长非常容易受到干扰，导致致命的后果，包括不完全复制、突变和基因组重排，这可能是细胞死亡、基因组疾病、肿瘤形成和进展的基础。尽管最大限度地减少DNA复制延长的中断很重要，但细胞如何做到这一点仍然知之甚少。我们最近采用全基因组、系统的方法，在革兰氏阳性杆菌枯草芽孢杆菌中鉴定了一种新的营养响应复制延伸调节。我们认为，这种调控使复制延长处于代谢控制之下，以防止复制中断，并与拯救和重新激活中断的复制叉子的机制一起，牢固地维持基因组的完整性。这样的机制很可能存在于其他生物体中，并发挥着比之前设想的更重要的作用。我们的目标是评估复制延伸调节的作用及其在其他细菌(如大肠杆菌)中的流行情况，并确定调节复制抑制和破坏性复制抑制之间的分子差异。我们的研究将有助于了解复制延伸复合体与其细胞环境之间的联系。这将加深对不受控制的复制在肿瘤发生和基因组疾病中的可能作用的理解，并阐明潜在的基因组完整性的基本原理。具体目标是：1.研究一种新的复制延长调控机制在枯草杆菌中的作用；2.确定复制分叉上不同复制抑制后的关键事件；3.描述在大肠杆菌中复制延长的控制。与公共卫生相关：我们发现了一种细菌控制其DNA复制的新方法。研究这一途径阐明了控制DNA复制的新的和保守的原则。失去这种控制可能会导致基因组重排和突变，这是几种人类基因组疾病和癌症的基础。了解这一途径对于了解微生物对抗生素耐药性的发展也很重要。