TEMPORAL AND SPATIAL CONTROL OF B SUBTILIS CYTOKINESIS

细胞如何决定何时何地分裂仍然是现代科学的一大谜团。 生物学在空间上，严格控制分隔，以确保隔片的准确定位。暂时来说， 分裂与细胞生长、DNA复制和染色体分离相协调，以确保 子细胞达到适当的大小并具有完整的基因组。从人类到 在细菌中，细胞分裂是通过在新生分裂时形成细胞骨架蛋白环来启动的。 绝佳的价钱该环确定了分隔隔膜的位置，并用作组装隔膜的框架。 除法器在细菌中，该环由必需的微管蛋白样GTftsZ组成。 细菌细胞分裂的精确控制是通过许多细胞因子的协同作用来实现的。 FtsZ组装动力学的因素。理解细菌的时空调控 因此，分裂需要鉴定和表征调节FtsZ组装的因子。而 几种蛋白质已被证明可以阻止FtsZ在异常亚细胞位置的组装，但知之甚少 关于负责协调FtsZ环形成与细胞生长和DNA的机制 复制的此外，FtsZ的高细胞内浓度需要存在因子， 维持游离FtsZ亚基的库并保护环的动态性质。 这项建议有三个主要目标。第一，在基因和分子水平上剖析 负责通过调节FtsZ组装将细胞大小与营养可用性偶联的调节回路 动力学第二，分析细胞大小与细胞周期进程的关系，利用 一种能使细胞体积缩小35%的突变。第三，确定ATP非依赖性机制 ClpX分子伴侣通过其抑制FtsZ组装并维持游离FtsZ的细胞库 亚单位。 作为细菌细胞分裂机制的重要组成部分，FtsZ及其调控因子 活性是开发新抗生素的潜在目标。此外，这项工作应 不仅阐明了细菌细胞分裂，而且阐明了所有生物体基本胞质分裂的各个方面。 了解通常控制细胞分裂的分子机制将有助于确定它们失败的原因 在肿瘤发生期间，导致癌细胞的异常分裂和快速增殖特征。本建议旨在确定和描述作为下列要素的基本组成部分的因素： 细菌细胞分裂机制，因此有望成为 开发新的抗生素。虽然这些因素本身是独特的， 分裂表现出非凡的进化保守性，我们的工作将阐明 胞质分裂是所有生物的基础。了解分子机制， 正常控制的细胞分裂将有助于确定为什么它们在肿瘤发生过程中失败， 癌细胞的异常分裂和快速增殖特征。

How cells determine when and where to divide remains one of the great mysteries of modern biology. Spatially, division is tightly regulated to ensure the accurate positioning of septa. Temporally, division is coordinated with cell growth, DNA replication, and chromosome segregation to ensure that daughter cells reach the appropriate size and have complete genomes. In organisms from humans to bacteria, cell division is initiated by the formation of a ring of a cytoskeletal protein at the nascent division site. This ring establishes the location of the division septum and serves as a framework for assembly of the division apparatus. In bacteria this ring is composed of the essential tubulin-like GTPase FtsZ. The precise control of bacterial cell division is achieved through the concerted actions of numerous factors on FtsZ assembly dynamics. Comprehending the spatial and temporal regulation of bacterial division, thus, requires the identification and characterization of factors that modulate FtsZ assembly. While several proteins have been shown to prevent FtsZ assembly at aberrant subcellular locations, little is known about the mechanisms responsible for coordinating FtsZ ring formation with cell growth and DNA replication. Moreover, the high intracellular concentration of FtsZ demands the presence of factors that maintain the pool of free FtsZ subunits and protect the dynamic nature of the ring. This proposal has three major goals. One, to dissect at the genetic and molecular level the regulatory circuit responsible for coupling cell size to nutritional availabilty by modulating FtsZ assembly dynamics. Two, to analyze the relationship between cell size and cell cycle progression, taking advantage of a mutation that reduces cell size by ~35%. And, three, to determine the ATP-independent mechanism through which the ClpX chaperone inhibits FtsZ assembly and maintains the cellular pool of free FtsZ subunits. As essential components of the bacterial cell division machinery, FtsZ and the factors governing its activity are potential targets for the development of new antibiotics. Furthermore, this work should illuminate not only bacterial cell division, but also aspects of cytokinesis fundamental to all organisms. Understanding the molecular mechanisms that normally control cell division will help identify why they fail during oncogenesis, leading to the aberrant divisions and rapid proliferation characteristic of cancer cells. This proposal seeks to identify and characterize factors that are essential components of the bacterial cell division machinery, and thus hold promise as potential targets for the development of new antibiotics. While the factors themselves are unique, mechanistically cell division exhibits extraordinary evolutionary conservation and our work will illuminate aspects of cytokinesis fundamental to all organisms. Understanding the molecular mechanisms that normally control cell division will help identify why they fail during oncogenesis, leading to the aberrant divisions and rapid proliferation characteristic of cancer cells.