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.
Showing the most recent 10 out of 30 publications
