title: Discrete gene replication events drive coupling between the cell cycle and circadian clocks.
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 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.
authors.affiliation: FOM Institute AMOLF, 1098 XG Amsterdam, The Netherlands; Department of Physics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Joris
authors.initials: J
authors.lastname: Paijmans
authors.affiliation: FOM Institute AMOLF, 1098 XG Amsterdam, The Netherlands;
authors.forename: Mark
authors.initials: M
authors.lastname: Bosman
authors.affiliation: FOM Institute AMOLF, 1098 XG Amsterdam, The Netherlands; tenwolde@amolf.nl dkluben@umich.edu.
authors.forename: Pieter Rein
authors.initials: PR
authors.lastname: Ten Wolde
authors.affiliation: Department of Physics, University of Michigan, Ann Arbor, MI 48109 tenwolde@amolf.nl dkluben@umich.edu.
authors.forename: David K
authors.initials: DK
authors.lastname: Lubensky
mesh_terms: D002453:Cell Cycle / Q000235:genetics*; D057906:Circadian Clocks / Q000235:genetics*; D005798:Genes, Bacterial; D046940:Synechococcus / Q000235:genetics*
keywords: Kai; cell cycle; circadian rhythms; oscillations; simulation