Synchronization of chromosome dynamics and cell division in bacteria

Abstract

Bacterial cells have evolved a variety of regulatory circuits that tightly synchronize their chromosome replication and cell division cycles, thereby ensuring faithful transmission of genetic information to their offspring. Complex multicomponent signaling cascades are used to monitor the progress of cytokinesis and couple replication initiation to the separation of the two daughter cells. Moreover, the cell-division apparatus actively participates in chromosome partitioning and, particularly, in the resolution of topological problems that impede the segregation process, thus coordinating chromosome dynamics with cell constriction. Finally, bacteria have developed mechanisms that harness the cell-cycle-dependent positioning of individual chromosomal loci or the nucleoid to define the cell-division site and control the timing of divisome assembly. Each of these systems manages to integrate a complex set of spatial and temporal cues to regulate and execute critical steps in the bacterial cell cycle.

Figure 1.

Synchronization of replication initiation with cell division in C. crescentus. (A) Monitoring of cell division via the phosphorylation state of DivK. In dividing cells, the histidine kinase DivJ and the bifunctional histidine kinase/phosphatase PleC form complexes that are localized to the stalked and the flagellated pole, respectively. At this stage, both proteins function as kinases, ensuring a high concentration of DivK∼P within the cell. After cell division, PleC switches from the kinase to the phosphatase mode. The DivK molecules captured in the swarmer sibling are thus dephosphorylated, whereas those remaining in the stalked sibling are still retained in the phosphorylated state. (B) Role of DivK in the regulation of replication initiation. Dephosphorylated DivK activates a signaling cascade that leads to the phosphorylation of the response regulators CtrA and CpdR. CtrA∼P binds to five sites within the origin of replication, thereby inhibiting replication initiation. Formation of CpdR∼P prevents proteolysis of CtrA∼P and thus reinforces the block of chromosome replication.

Figure 2.

Role of KOPS-regulated DNA translocation by FtsK in the final steps of chromosome segregation. (A) Effect of KOPS (FtsK-orienting polar sequences) on the direction of FtsK movement. The boxed sequence indicates the E. coli KOPS consensus motif. Hexameric rings, assembled from the carboxy-terminal portions of different FtsK molecules (FtsK_C), load onto DNA in a KOPS-dependent manner, and then translocate in the direction determined by the polarity of the KOPS elements (green arrows). (B) Stimulation of chromosome decatenation by FtsK. Translocation of FtsK_C toward the terminal dif site positions catenanes at the cell-division plane. Unlinking of the two chromosomes is catalyzed by topoisomerase IV, a tetrameric enzyme composed of the proteins ParC (red spheres) and ParE (blue spheres). FtsK directly interacts with ParC, thereby concentrating the activity of topoisomerase IV to the vicinity of the cell-division site. (C) Role of FtsK in chromosome dimer resolution. The translocase activity of FtsK_C moves the two dif sites of a chromosome dimer to the cell-division plane, thereby promoting formation of a productive recombination synapse. In addition, FtsK_C directly interacts with the recombinase XerD (green spheres) and thus induces the first pair of strand exchanges. The recombinase XerC (blue spheres) then completes the recombination reaction, restoring the two original chromosomes.

Figure 3.

Model for the positioning of the FtsZ ring by the nucleoid occlusion and Min systems in E. coli. (A) Temporal and spatial regulation of cell division by nucleoid occlusion. The nucleoid occlusion protein SlmA preferentially associates with the pole-proximal regions of the nucleoid. At the beginning of the division cycle, the longitudinal dimensions of the nucleoid are small, thereby placing SlmA close to midcell and blocking FtsZ ring assembly. In the course of chromosome replication and segregation, the two nascent daughter nucleoids move apart. As a consequence, the midcell region is cleared of SlmA, allowing FtsZ polymerization to occur. (B) Inhibition of polar cell-division events by the Min system. MinD, bound to the cell division inhibitor MinC, assembles on the cytoplasmic membrane, forming a cap-like polymeric layer that prevents FtsZ ring formation in the polar region of the cell. MinE is organized into a ring-shaped structure that gradually displaces MinCD from the membrane. Free MinC and MinD subunits reassemble at the opposite cell pole, thus establishing a new polar cap and restarting the cycle. (C) Cooperation of the nucleoid occlusion and Min systems. The combined action of SlmA and the Min system targets the FtsZ ring to midcell and ensures that divisome formation is delayed to the final phase of the replication cycle.

Figure 4.

Division site placement by the MipZ · ParB system. The cell division regulator MipZ forms a complex with the DNA-binding protein ParB close to the chromosomal origin of replication, located at the stalked pole of the cell. FtsZ, by contrast, assembles into a polymer that is localized to the pole opposite the stalk. Chromosome replication generates two copies of the origin region, which immediately reassociate with the MipZ · ParB complex and then move apart toward the cell poles. As a consequence, a gradient of MipZ is established, with its concentration being highest in proximity of the two segregated origin regions and lowest at midcell. Owing to the inhibitory effect of MipZ on FtsZ polymerization, the polar FtsZ complex disintegrates and a new polymer is formed at the cell center (adapted from Thanbichler and Shapiro 2006).