How cells determine when and where to divide is one of the great questions in modern biology. Spatially, division is tightly regulated to ensure th accurate positioning of septa. Temporally, division is coordinated with cell growth, DNA replication, and chromosome segregation to ensure that daughter cells are the appropriate size and have complete genomes. In organisms from humans to bacteria, cells initiate division by the formation of a cytoskeletal protein ring at the nascent division site. In bacteria this ring is composed of the essential tubulin-like GTPase FtsZ. Bacteria achieve precise control over division primarily through the concerted actions of factors that modulate 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 we have begun to understand the factors responsible for preventing FtsZ assembly at aberrant subcellular locations and for maintaining integrity of the FtsZ ring, much less is known about the mechanisms responsible for coordinating FtsZ ring formation with cell growth and the cell cycle. This proposal has three primary objectives: first, to dissect the nutrient-dependent mechanisms governing the activity of UgtP and OpgH, division inhibitors that contribute to growth rate-dependent increases in cell size in B. subtilis and E. coli respectively; second, to identify and characterize additional components of the regulatory circuit responsible for E. coli cell size homeostasis; and, third, to assess the contribution of FtsZ's unstructured C-terminal domain -- a primary site of interaction between FtsZ and its modulatory proteins -- to the assembly and integrity of the cytokinetic ring via an integrated approach employing genetics, biochemistry, and superresolution microscopy. This project should also help shed light upon questions of broader scientific importance. FtsZ and the factors governing its activity are essential components of the bacterial cell division machinery and are therefore attractive targets for the development of new antibiotics. Furthermore, comparative analysis of the factors responsible for the spatial and temporal control of cell division in E. coli and B. subtilis, two highly divergent model organisms, promises to reveal underlying aspects of cell cycle regulation fundamental to all domains of life. Finally, understanding the molecular mechanisms that normally control cell division should help identify why these mechanisms fail during oncogenesis, and lead to the aberrant divisions and rapid cell proliferation characteristic of cancer.
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.
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