title: Robust circadian clocks from coupled protein-modification and transcription-translation cycles.
abstract: The cyanobacterium Synechococcus elongatus uses both a protein phosphorylation cycle and a transcription-translation cycle to generate circadian rhythms that are highly robust against biochemical noise. We use stochastic simulations to analyze how these cycles interact to generate stable rhythms in growing, dividing cells. We find that a protein phosphorylation cycle by itself is robust when protein turnover is low. For high decay or dilution rates (and compensating synthesis rates), however, the phosphorylation-based oscillator loses its integrity. Circadian rhythms thus cannot be generated with a phosphorylation cycle alone when the growth rate, and consequently the rate of protein dilution, is high enough; in practice, a purely posttranslational clock ceases to function well when the cell doubling time drops below the 24-h clock period. At higher growth rates, a transcription-translation cycle becomes essential for generating robust circadian rhythms. Interestingly, although a transcription-translation cycle is necessary to sustain a phosphorylation cycle at high growth rates, a phosphorylation cycle can dramatically enhance the robustness of a transcription-translation cycle at lower protein decay or dilution rates. In fact, the full oscillator built from these two tightly intertwined cycles far outperforms not just each of its two components individually, but also a hypothetical system in which the two parts are coupled as in textbook models of coupled phase oscillators. Our analysis thus predicts that both cycles are required to generate robust circadian rhythms over the full range of growth conditions.
authors.affiliation: FOM (Stichting voor Fundamenteel Onderzoek der Materie) Institute for Atomic and Molecular Physics (AMOLF), Science Park 104, 1098 XG Amsterdam, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Zwicker
authors.forename: David K
authors.initials: DK
authors.lastname: Lubensky
authors.forename: Pieter Rein
authors.initials: PR
authors.lastname: ten Wolde
mesh_terms: D000465:Algorithms; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D013269:Stochastic Processes; D046940:Synechococcus / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D001426:Bacterial Proteins; D056925:Circadian Rhythm Signaling Peptides and Proteins; C114269:KaiA protein, cyanobacteria; C114270:KaiB protein, cyanobacteria; C114271:KaiC protein, cyanobacteria