Journal of Biochemistry Advance Access originally published online on September 29, 2006
Journal of Biochemistry 2006 140(5):609-617; doi:10.1093/jb/mvj198
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© 2006 The Japanese Biochemical Society.
JB Review |
Regulating a Circadian Clock's Period, Phase and Amplitude by Phosphorylation: Insights from Drosophila
1 Kiho Bae, Department of Life Science, Yonsei University, Wonju, 220-710 Korea; and 2 Isaac Edery, Department of Molecular Biology and Biochemistry, Rutgers University, Center for Advanced Biotechnology and Medicine, 679 Hoes Lane, Piscataway, NJ 08854, USA
* To whom correspondence should be addressed. Tel: +82-33-760-2280, Fax: +82-33-760-2183, E-mail: kbae{at}yonsei.ac.kr
Much progress has been made in understanding the molecular underpinnings governing circadian (
24 h) rhythms. Despite the increased complexity in metazoans whereby inter-cellular networks form the basis for driving overt rhythms, such as wake–sleep cycles in animals, single isolated cells can exhibit all the formal properties of a circadian pacemaker. How do these cell-autonomous rhythm generators operate? Breakthrough studies in Drosophila melanogaster led to the realization that the molecular logic underlying circadian clocks are highly shared. Most notably, interconnected transcriptional-translational feedback loops produce coordinated rhythms in "clock" RNAs and proteins that are required for the daily progression of clocks, synchronization to local time and transducing temporal signals to downstream effector pathways. More recent findings indicate prominent roles for reversible phosphorylation of clock proteins in the core oscillatory mechanism. In this review we focus on findings in Drosophila to explore the multiple levels that reversible phosphorylation plays in clock function. Specific clock proteins in this system are subjected to different phosphorylation programs, which affect three key properties of a circadian oscillator, its period, amplitude and phase. The role of phosphorylation in clocks is of clear relevance to human health because mutations that affect the PERIOD (PER) phosphorylation program are associated with familial sleep disorders. In addition, the central role of phosphorylation in the assembly of a circadian oscillator was dramatically shown recently by the ability to reconstitute a circadian phosphorylation/dephosphorylation cycle in vitro, suggesting that the dynamics of clock protein phosphorylation are at the "heart" of circadian time-keeping.
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