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

TL;DR

This study uses mathematical modeling to reveal how gene replication events during the cell cycle can influence circadian clocks, potentially disrupting their function, and discusses mechanisms in cyanobacteria that mitigate this effect.

Contribution

The paper demonstrates that gene copy number changes during the cell cycle can non-specifically drive circadian clocks, and identifies features that protect cyanobacterial clocks from such disturbances.

Findings

Gene replication causes periodic driving of circadian clocks.

Negative feedback clocks can lock to the cell cycle or behave erratically.

Cyanobacteria have evolved mechanisms to insulate their clocks from cell cycle effects.

Abstract

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 non-specific 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 the different phosphoforms, makes the clock less susceptible to perturbations in protein synthesis; and the presence of multiple, asynchronously replicating copies of the same chromosome diminishes the effect of replicating any single copy of a gene.