Functioning biological clock unravelled

In the online Early Edition of the Proceedings of the National Academy of Sciences USA, researchers from the FOM Institute AMOLF and the University of Michigan, Ann Arbor, present a mathematical model that explains how the biological clock can remain robust under different growth conditions.Many organisms use circadian clocks to anticipate the changes between day and night. These clocks are reset on a daily basis under the influence of light – the cause of your jet lag when you travel to another continent – but even in the absence of any daily cue, these clocks can maintain robust rhythms for months, or even years. However, nobody knew how these clocks can be so stable.

It had long been believed that circadian clocks are primarily driven by cycles of protein synthesis and protein degradation. Interestingly, in 2005 the Kondo group from Japan showed that cyanobacteria exhibit a protein modification cycle with a period of 24 hours. A few years later, the same group showed that when they stopped the protein modification oscillations, the oscillations in protein synthesis still persisted with a period of 24 hours. This unambiguously showed that the circadian clock is driven by both a protein modification cycle and a protein synthesis cycle. The question that therefore arose was: why does the clock have these two cycles?

The model developed by the researchers shows that the coupling of a protein modification and a protein synthesis cycle allows for robust circadian rhythms under different growth conditions. At high growth rates, a lot of new proteins have to be synthesised. If these were to be synthesised at constant rates, the protein modification oscillations would be destroyed. The crux of the protein synthesis oscillator is that it allows the bacteria to make new proteins only when the protein modification oscillations are in phase with the modification state of the freshly made proteins. Therefore at high growth rates a protein synthesis oscillator is essential for sustaining a protein modification oscillator. Conversely, the model reveals that at low growth rates the protein synthesis oscillator can also enhance the robustness of the protein modification oscillator. In fact, the coupled system can be an order of magnitude more stable than each of the oscillators alone, an effect that cannot be observed with conventionally coupled phase oscillators. Since it is now clear that circadian clocks of higher organisms, like humans, often employ protein modification as well, the researchers believe that their results also apply to our circadian clock.

Information
Prof. Dr.  Pieter Rein ten Wolde (FOM-Instituut AMOLF), tenwoldeATamolf.nl, +31 20 754 7281.

Reference
'Robust circadian clocks from coupled protein modification and protein transcription-translation cycles' ,
David Zwicker, David K. Lubensky, Pieter Rein ten Wolde,
Proc. Natl. Acad. Sci. USA, Early Online, December 13, 2010.

Figure 1: The figure depicts clocks that degrade over time, but are replaced every 24 hours. This symbolises the coupling between the protein modification cycle and the protein synthesis and degradation cycle of the circadian clock in growing, dividing cells of the cyanobacterium S. elongatus.