Biology and Biomedical Sciences: Molecular Genetics and Genomics
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
Petra A Levin
During the cell cycle, a cell must replicate its DNA, segregate the genome and divide into two identical daughter cells with full chromosomes. This process needs to be specifically coordinated to ensure that cell division does not occur before DNA replication has finished and that the cell septates precisely at midcell to segregate one chromosome to each daughter cell. If cells divide before the chromosome is fully replicated, the chromosome could be guillotined or cell division could occur resulting in cells without chromosomes. If division does not occur properly, the cells elongate but do not divide and form multinucleate filaments.
In wild-type cells, DNA replication and cell division appear to be perfectly coordinated. Even at faster doubling times, the cell cycle is synchronized so that DNA replication initiates and terminates once per cell division, the cell division protein FtsZ assembles into a ring precisely at midcell, and cell septation only occurs once the chromosome has replicated and segregated. Despite this apparent coordination, the long-held view in the field is that cell division and DNA replication are independent cycles that are merely coordinated during normal growth. However, it remains widely accepted that cell division is independent from DNA replication in bacteria.
In this dissertation, I make 3 contributions to the field of cell cycle regulation. First, I identify a control point that couples cell division with the initiation of DNA replication. Second, I show that long-term inhibitions of cell division lead to terminal cell cycle arrest at a time we have termed the "Point of no return" or PONR. The PONR is equivalent to the eukaryotic G0 arrest and validates the development of antibiotics that target the cell division machinery. Third, I characterized determinants for assembly of the tubulin-like protein FtsZ using a genetic approach. This work enhances our understanding of what is critical for FtsZ function in vivo and highlights the need to develop better assays for evaluating FtsZ assembly in vitro.
Arjes, Heidi Ann, "Failsafe Mechanisms Coordinate Cell Division and the Initiation of DNA Replication in Bacteria" (2014). All Theses and Dissertations (ETDs). 1280.