Abstract
In the Drosophila circadian clock, Period (PER) and Timeless (TIM) proteins inhibit Clock-mediated transcription of per and tim genes until PER is degraded by Doubletime/CK1 (DBT)-mediated phosphorylation, establishing a negative feedback loop. Multiple regulatory delays within this feedback loop ensure ~24 hr periodicity. Of these delays, the mechanisms that regulate delayed PER degradation (and Clock reactivation) remain unclear. Here we show that phosphorylation of certain DBT target sites within a central region of PER affect PER inhibition of Clock and the stability of the PER/TIM complex. Our results indicate that phosphorylation of PER residue S589 stabilizes and activates PER inhibitory function in the presence of TIM, but promotes PER degradation in its absence. The role of DBT in regulating PER activity, stabilization and degradation ensures that these events are chronologically and biochemically linked, and contributes to the timing of an essential delay that influences the period of the circadian clock.
Highlights
The proteins that comprise circadian clocks are largely conserved across the animal kingdom (Crane and Young, 2014; Young and Kay, 2001; Zheng and Sehgal, 2012)
PER S589 substitutions are associated with short-period rhythmic behavior
These results suggest that both phosphorylation and loss of phosphorylation at S589 normally contribute to the post-transcriptional delays that regulate circadian period length
Summary
The proteins that comprise circadian clocks are largely conserved across the animal kingdom (Crane and Young, 2014; Young and Kay, 2001; Zheng and Sehgal, 2012). These clocks, which promote daily rhythms in behavior and physiology, involve cell-autonomous, transcription-translation feedback loops that oscillate with ~24 hr periodicity. In Drosophila, the activator complex consists of dClock/Cycle (dCLK/CYC), which initiates transcription of period (per) and timeless (tim). PER and TIM proteins assemble to form an inhibitory complex in the cytoplasm that, after a delay, enters the nucleus to inhibit dCLK/CYC activity. The delay in transcriptional activation is critical for maintaining ~24 hr rhythmicity, its regulatory mechanisms are not well understood
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