Discrete gene replication events drive coupling between the cell cycle and circadian clocks

Significance Huygens famously showed that two mechanically connected clocks tend to tick in synchrony. We uncovered a generic mechanism that can similarly phase-lock two rhythmic systems present in many living cells: the cell cycle and the circadian clock. DNA replication during the cell cycle causes protein synthesis rates to show sharp, periodic jumps that can entrain the clock. To faithfully keep time in the face of these disturbances, circadian clocks must incorporate specific insulating mechanisms. We argue that, in cyanobacteria, the presence of multiple, identical chromosome copies and the clock’s core protein-modification oscillator together play this role. Our results shed new light on the complex factors that constrain the design of biological clocks. Many organisms possess both a cell cycle to control DNA replication and a circadian clock to anticipate changes between day and night. In some cases, these two rhythmic systems are known to be coupled by specific, cross-regulatory interactions. Here, we use mathematical modeling to show that, additionally, the cell cycle generically influences circadian clocks in a nonspecific fashion: The regular, discrete jumps in gene-copy number arising from DNA replication during the cell cycle cause a periodic driving of the circadian clock, which can dramatically alter its behavior and impair its function. A clock built on negative transcriptional feedback either phase-locks to the cell cycle, so that the clock period tracks the cell division time, or exhibits erratic behavior. We argue that the cyanobacterium Synechococcus elongatus has evolved two features that protect its clock from such disturbances, both of which are needed to fully insulate it from the cell cycle and give it its observed robustness: a phosphorylation-based protein modification oscillator, together with its accompanying push–pull read-out circuit that responds primarily to the ratios of different phosphoform concentrations, makes the clock less susceptible to perturbations in protein synthesis; the presence of multiple, asynchronously replicating copies of the same chromosome diminishes the effect of replicating any single copy of a gene.