Control of elongation of DNA replication

项目摘要 DNA复制延长的控制 准确、完整的DNA复制对所有人来说都至关重要 有机体复制延伸非常容易受到破坏， 包括不完全复制、突变和基因组在内的致命后果 重排，这可能是细胞死亡，基因组疾病，肿瘤 形成和发展。尽管尽量减少干扰的重要性， DNA复制延长，细胞如何做到这一点仍然很差 明白我们最近采用了全基因组的系统方法， 确定了一种新的营养反应性调节复制延长在 革兰氏阳性菌枯草芽孢杆菌。我们建议，这项规例 在代谢控制下的复制延长以防止复制中断， 以及拯救和重新激活被破坏的机制， 复制叉，稳健地维持基因组完整性。这种机制 可能存在于其他生物体中，并且发挥着比 以前设想的。我们的目标是评估复制调控的作用 延伸，其在其他细菌如E.大肠杆菌，并定义 受调控的复制停滞和破坏性复制之间的分子差异 复制逮捕。我们的研究将大大有助于了解 复制延伸复合物和其细胞之间的连接 环境这将加深对以下方面可能发挥的作用的理解： 不受控制的复制在肿瘤发生和基因组疾病，并阐明 基因组完整性的基本原则。具体目标是：1. 研究B中复制延长的新调节机制的作用。 枯草芽孢杆菌; 2.在复制分叉处描述关键事件， 复制抑制; 3.描述了E.杆菌

Project Summary Control of elongation of DNA replication 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.