Abstract
Author SummaryCircadian clocks adjust the physiology and behavior of organisms to the day/night cycle and rely on molecular feedback loops that generate daily oscillations of transcription. In the Drosophila fruit fly, the PERIOD (PER) and TIMELESS (TIM) proteins coordinate the clock–they accumulate during the night, form a complex, and repress their own gene expression in the early morning. The temporal control of this oscillation involves the phosphorylation, ubiquitination, and proteasomal degradation of the PER and TIM proteins. The SUPERNUMERARY LIMBS (SLMB) ubiquitin ligase is known to play a key role in controlling the degradation of phosphorylated PER and TIM. In this study we investigated the role of another ubiquitin ligase, CULLIN-3 (CUL-3). We found that inhibition of CUL-3 activity results in the abolition of rest/activity rhythms in flies and flattens the PER and TIM oscillations. CUL-3 physically interacts and forms a complex with a lowphosphorylated version of TIM in the absence of PER, thereby allowing its accumulation during the night. In contrast, when PER is present SLMB preferentially interacts with phosphorylated TIM, favoring its degradation. The results suggest that CUL-3 and SLMB share the work to control the oscillations of the PER and TIM proteins during the day/night cycle.
Highlights
Circadian clocks are present in most living organisms and control a variety of physiological and behavioral functions
In this study we investigated the role of another ubiquitin ligase, CULLIN-3 (CUL-3)
We found that inhibition of CUL-3 activity results in the abolition of rest/activity rhythms in flies and flattens the PER and TIM oscillations
Summary
Circadian clocks are present in most living organisms and control a variety of physiological and behavioral functions. The accumulation of the repressor proteins is delayed by post-translational mechanisms, allowing us to define active and inactive phases of transcription, an oscillation. In Drosophila, the two basic helix-loop-helix PERARNT-SIM (bHLH PAS) proteins CLOCK (CLK) and CYCLE (CYC) activate the transcription of their targets in the evening [2,3]. The target genes period (per) and timeless (tim) encode two proteins that associate in a complex, progressively accumulate, and become phosphorylated to repress CLK/CYC-dependent transcription in the late night. The delayed accumulation, nuclear entry, and transcriptional activity of PER and TIM involve their phosphorylation by several kinases such as DOUBLE TIME (DBT) CK1e [4,5,6,7,8,9,10] and NEMO [11] that target PER. Nuclear phosphorylated PER induces CLK phosphorylation and removal from the chromatin, PER degradation in the morning allows CLK-CYC-dependent transcription to resume [18,19,20,21]
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