Modularity of the Bacterial Cell Cycle Enables Independent Spatial and Temporal Control of DNA Replication

SummaryBackgroundComplex regulatory circuits in biology are often built of simpler subcircuits or modules. In most cases, the functional consequences and evolutionary origins of modularity remain poorly defined.ResultsHere, by combining single-cell microscopy with genetic approaches, we demonstrate that two separable modules independently govern the temporal and spatial control of DNA replication in the asymmetrically dividing bacterium Caulobacter crescentus. DNA replication control involves DnaA, which promotes initiation, and CtrA, which silences initiation. We show that oscillations in DnaA activity dictate the periodicity of replication while CtrA governs the asymmetric replicative fates of daughter cells. Importantly, we demonstrate that DnaA activity oscillates independently of CtrA.ConclusionsThe genetic separability of spatial and temporal control modules in Caulobacter reflects their evolutionary history. DnaA is the central component of an ancient and phylogenetically widespread circuit that governs replication periodicity in Caulobacter and most other bacteria. By contrast, CtrA, which is found only in the asymmetrically dividing α-proteobacteria, was integrated later in evolution to enforce replicative asymmetry on daughter cells.

Graphical AbstractFigure optionsDownload high-quality image (146 K)Download as PowerPoint slideHighlights
► CtrA and DnaA comprise two independent replication control modules in Caulobacter
► Perturbing CtrA activity mainly affects replicative asymmetry, but not periodicity
► Modulating DnaA activity shortens or prolongs replication periods
► The separability of the DnaA and CtrA modules reflects their evolutionary history