PER-dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription
- 1 Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5001, USA;
- 2 Center for Biological Clocks Research, Department of Biology, Texas A&M University, College Station, Texas 77843-3258, USA
Abstract
Transcriptional activation by CLOCK-CYCLE (CLK-CYC) heterodimers and repression by PERIOD-TIMELESS (PER-TIM) heterodimers are essential for circadian oscillator function in Drosophila. PER-TIM was previously found to interact with CLK-CYC to repress transcription, and here we show that this interaction inhibits binding of CLK-CYC to E-box regulatory elements in vivo. Coincident with the interaction between PER-TIM and CLK-CYC is the hyperphosphorylation of CLK. This hyperphosphorylation occurs in parallel with the PER-dependent entry of DOUBLE-TIME (DBT) kinase into a complex with CLK-CYC, where DBT destabilizes both CLK and PER. Once PER and CLK are degraded, a novel hypophosphorylated form of CLK accumulates in parallel with E-box binding and transcriptional activation. These studies suggest that PER-dependent rhythms in CLK phosphorylation control rhythms in E-box-dependent transcription and CLK stability, thus linking PER and CLK function during the circadian cycle and distinguishing the transcriptional feedback mechanism in flies from that in mammals.
Keywords
Footnotes
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↵3 Corresponding author.
↵3 E-MAIL phardin{at}mail.bio.tamu.edu; FAX (979) 845-2891.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1404406
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- Received December 22, 2005.
- Accepted January 25, 2006.
- Copyright © 2006, Cold Spring Harbor Laboratory Press