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Robust circadian clocks from coupled protein-modification and transcription—translation cycles

David Zwicker, David K. Lubensky, Pieter Rein ten Wolde and David R. Nelson
Proceedings of the National Academy of Sciences of the United States of America
Vol. 107, No. 52 (December 28, 2010), pp. 22540-22545
Stable URL: http://www.jstor.org/stable/25770675
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Robust circadian clocks from coupled protein-modification and transcription—translation cycles
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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.

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