Caulobacter Crescentus - Cell Cycle

Cell Cycle

The Caulobacter cell cycle regulatory system controls many modular subsystems that organize the progression of cell growth and reproduction. A control system constructed using biochemical and genetic logic circuitry organizes the timing of initiation of each of these subsystems. The central feature of the cell cycle regulation is a cyclical genetic circuit—a cell cycle engine –- that is centered around the successive interactions of four master regulatory proteins: DnaA, GcrA, CtrA, and CcrM. These four proteins directly control the timing of expression of over 200 genes. The four master regulatory proteins are synthesized and then eliminated from the cell one after the other over the course of the cell cycle. Several additional cell signaling pathways are also essential to the proper functioning of this cell cycle engine. The principal role of these signaling pathways is to ensure reliable production and elimination of the CtrA protein from the cell at just the right times in the cell cycle.

An essential feature of the Caulobacter cell cycle is that the chromosome is replicated once and only once per cell cycle. This is in contrast to the E. coli cell cycle where there can be overlapping rounds of chromosome replication simultaneously underway. The opposing roles of the Caulobacter DnaA and CtrA proteins are essential to the tight control of Caulobacter chromosome replication. The DnaA protein acts at the origin of replication to initiate the replication of the chromosome. The CtrA protein, in contrast, acts to block initiation of replication, so it must be removed from the cell before chromosome replication can begin. Multiple additional regulatory pathways integral to cell cycle regulation and involving both phospho signaling pathways and regulated control of protein proteolysis act to assure that DnaA and CtrA are present in the cell just exactly when needed.

Each process activated by the proteins of the cell cycle engine involves a cascade of many reactions. The longest subsystem cascade is DNA replication. In Caulobacter cells, replication of the chromosome involves about 2 million DNA synthesis reactions for each arm of the chromosome over 40 to 80 min depending on conditions. While the average time for each individual synthesis reaction can be estimated from the observed average total time to replicate the chromosome, the actual reaction time for each reaction varies widely around the average rate. This leads to a significant and inevitable cell-to-cell variation time to complete replication of the chromosome. There is similar random variation in the rates of progression of all the other subsystem reaction cascades. The net effect is that the time to complete the cell cycle varies widely over the cells in a population even when they all are growing in identical environmental conditions. Cell cycle regulation includes feedback signals that pace progression of the cell cycle engine to match progress of events at the regulatory subsystem level in each particular cell. This control system organization, with a controller (the cell cycle engine) driving a complex system, with modulation by feedback signals from the controlled system creates a closed loop control system.

The rate of progression of the cell cycle is further adjusted by additional signals arising from cellular sensors that monitor environmental conditions (for example, nutrient levels and the oxygen level) or the internal cell status (for example, presence of DNA damage).