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 transcriptiontranslation 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.

Circadian Rhythms in Cyanobacteria

“…Moreover, experiments in which kaiBC was placed under the control of an exogenous promoter in order to eliminate the TTFL showed that, under conditions that favor rapid growth, enhanced variations in phase are observed among individual cells within the population (61). These data, coupled with mathematical modeling, suggest that the TTFL is required for the generation of robust circadian oscillations specifically under conditions of rapid growth (61,62). In contrast to what is observed in eukaryotic systems, the phasing of the cyanobacterial clock is inherited from mother cell to daughter cell with negligible intercellular coupling (63,64).…”

The elongation rate of RNA polymerase II in zebrafish and its significance in the somite segmentation clock

“…Studies of circadian clocks have revealed other precedents. For example, the cyanobacterium Synechococcus possesses both a transcriptional oscillator and an enzymatic phosphorylation/ dephosphorylation oscillator that is independent of transcription; these are normally coupled, but each can generate a circadian rhythm in the absence of the other (Kitayama et al, 2008;Zwicker et al, 2010). Moreover, many organisms, from bacteria to mammals, contain a non-transcriptional oxidation/reduction circadian oscillator that operates in parallel with a transcriptional circadian oscillator (Edgar et al, 2012).…”

Daily Rhythms in the Cyanobacterium Synechococcus elongatus Probed by High-resolution Mass Spectrometry–based Proteomics Reveals a Small Defined Set of Cyclic Proteins

“…However, it has been shown to encompass a transcription/translation feedback loop in which the KaiABC genes and their products participate in positive and negative autoregulatory feedback loops (10,11), similar to what is observed in higher organisms (12). Different studies connect the KaiABC central clock with control over transcriptional activity through different effectors such as the histidine kinase Synechococcus adaptative sensor A, the putative transcription factor regulator of phycobilisome-associated A (13,14), the regulator of phycobilisome-associated B regulator (15), low amplitude and bright A, the sensor histidine kinase circadian input kinase A (16,17), and the input factors Pex and light-dependent period A.…”