Deciphering the molecular circuitry that controls cell cycle progression in bacteria

维持基因组的完整性对于细胞生存至关重要。为了完成这一重要任务，主要细胞 包括染色体复制、分离和胞质分裂的适当时机在内的周期事件都经过精心设计 协调、时间和空间。任何干扰这种协调的缺陷都可能是致命的。虽然 细菌的复制、分离和细胞分裂已被广泛研究，我们对如何进行复制、分离和细胞分裂的理解 这些进程的协调仍然有限。细菌的生存还取决于它们的能力 协调细胞周期进程与环境波动。在这个项目中，我们关注的是保守的 染色体复制起始蛋白 DnaA 及其非复制功能。长期目标是 表征协调细胞周期进程的调节因子的分子功能，从而 代表潜在的药物靶点。该项目的总体目标是定义用于 使用以下方法在时间上协调染色体复制的开始与细胞周期的进展 细菌模型系统新月柄杆菌。中心假设是 DnaA 控制 参与染色体分离和细胞大小决定的关键调节因子。目标 1 的重点是 通过表征 DnaA 如何协调染色体复制与分离的开始 细胞周期中 DnaA 与染色体位点着丝粒的物理关联。重点是 目标 2 是定义将 DnaA 活性与细胞大小调节及其依赖性联系起来的分子网络 关于营养的可用性。从该项目中收集的信息将为战略提供宝贵的见解 细菌利用它们在时间和空间上协调对细菌至关重要的多种机制 细胞存活。

Maintaining the integrity of the genome is essential to cell survival. To accomplish this vital task, major cell cycle events including chromosome replication, segregation, and proper timing of cytokinesis are exquisitely coordinated, temporally and spatially. Any defect that disturbs this coordination can be lethal. Although replication, segregation, and cell division have been extensively studied in bacteria, our understanding of how these processes are coordinated remains limited. Bacteria’s survival also depends on their ability to coordinate cell cycle progression with environmental fluctuations. In this project, we focus on the conserved chromosome replication initiator protein DnaA and its non-replicative functions. The long-term goal is to characterize the molecular functions of regulators that coordinate the progression of the cell cycle and thus represent potential drug targets. The overall objective of this project is to define the mechanisms used to temporally coordinate the onset of chromosome replication with the progression of the cell cycle using the bacterial model system Caulobacter crescentus. The central hypothesis is that DnaA controls the activity of key regulators involved in chromosome segregation and cell size determination. The focus of Aim 1 is to define how DnaA coordinates chromosome replication with the onset of segregation by characterizing the physical association of DnaA with the chromosomal locus the centromere over the cell cycle. The focus of Aim 2 is to define the molecular network that links DnaA’s activity to cell size regulation and its dependency on nutrient availability. Information garnered from this project will provide valuable insights into strategies used by bacteria to temporally and spatially coordinate the multiple mechanisms that are fundamental for the cell survival.