title: A PERIOD inhibitor buffer introduces a delay mechanism for CLK/CYC-activated transcription.
abstract: We investigated the functions of clock genes period (per) and timeless (tim) in establishing negative feedback on circadian transcription factors clock/cycle (Clk/cyc) in Drosophila. We show that PER protein persists for several hours after rapid degradation of TIM in the morning. We observed in cell culture that isolated PER inhibits CLK/CYC-activated transcription in the absence of TIM and we further demonstrated for the first time in vivo that PER accumulation in a tim loss-of-function mutant background causes efficient inhibition of CLK/CYC-dependent transcription. These results identify PER to be the main inhibitor for CLK/CYC and they suggest a delay mechanism during early morning, when PER protein, after degradation of TIM, forms an inhibitor buffer for CLK/CYC that attenuates the restart of the next cycle of CLK/CYC-activated transcription. While TIM likely enhances the inhibition of CLK/CYC by PER in the dark, our results suggest a reduction of PER-mediated inhibition by TIM in light.
authors.affiliation: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. fweber@scripps.edu
authors.forename: Frank
authors.initials: F
authors.lastname: Weber
authors.forename: Steve A
authors.initials: SA
authors.lastname: Kay
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology; D003624:Darkness; D004330:Drosophila / Q000166:cytology / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D005246:Feedback / Q000502:physiology; D005786:Gene Expression Regulation; D017344:Genes, Insect; D017930:Genes, Reporter / Q000235:genetics; D008027:Light; D008156:Luciferases / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D029721:Drosophila Proteins; D014157:Transcription Factors; D008156:Luciferases