Abstract
Protein phosphorylation plays an essential role in the generation of circadian rhythms, regulating the stability, activity, and subcellular localization of certain proteins that constitute the biological clock. This study examines the role of the protein kinase Doubletime (DBT), a Drosophila ortholog of human casein kinase I (CKI)ɛ/δ. An enzymatically active DBT protein is shown to directly phosphorylate the Drosophila clock protein Period (PER). DBT-dependent phosphorylation sites are identified within PER, and their functional significance is assessed in a cultured cell system and in vivo. The per S mutation, which is associated with short-period (19-h) circadian rhythms, alters a key phosphorylation target within PER. Inspection of this and neighboring sequence variants indicates that several DBT-directed phosphorylations regulate PER activity in an integrated fashion: Alternative phosphorylations of two adjoining sequence motifs appear to be associated with switch-like changes in PER stability and repressor function.
Highlights
Circadian rhythms (;24-h rhythms) in physiology and behavior are observed in almost all phyla
In certain cases cycling clock gene transcription can be eliminated without suppressing circadian rhythmicity, protein phosphorylation appears to be essential for persistent clock function [2]
Most proteins involved in circadian transcriptional feedback loops undergo reversible chemical modifications that regulate their activity in a time-of-day–dependent manner
Summary
Circadian rhythms (;24-h rhythms) in physiology and behavior are observed in almost all phyla. Plants, and animals, cell autonomous, autoregulatory gene and protein interactions promote circadian molecular oscillations. Most of the genes and proteins that make up such clocks are not conserved between phyla, suggesting that circadian clocks may have evolved independently in bacteria, fungi, plants. Notable exceptions are the protein kinases CK1 and CK2. The former is known to play a central role in both animal and fungal clocks, while CK2 has been shown to be essential for animal and plant circadian rhythmicity [1]. In certain cases cycling clock gene transcription can be eliminated without suppressing circadian rhythmicity, protein phosphorylation appears to be essential for persistent clock function [2]
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