title: NEMO kinase contributes to core period determination by slowing the pace of the Drosophila circadian oscillator.
abstract: The Drosophila circadian oscillator is comprised of transcriptional feedback loops that are activated by CLOCK (CLK) and CYCLE (CYC) and repressed by PERIOD (PER) and TIMELESS (TIM) [1]. The timing of CLK-CYC activation and PER-TIM repression is regulated posttranslationally, in part through rhythmic phosphorylation of CLK, PER, and TIM [2-4]. Although kinases that control PER and TIM levels and subcellular localization have been identified [5-10], additional kinases are predicted to target PER, TIM, and/or CLK to promote time-specific transcriptional repression. We screened for kinases that alter circadian behavior via clock cell-directed RNA interference (RNAi) and identified the proline-directed kinase nemo (nmo) as a novel component of the circadian oscillator. Both nmo RNAi knockdown and a nmo hypomorphic mutant shorten circadian period, whereas nmo overexpression lengthens circadian period. CLK levels increase when nmo expression is knocked down in clock cells, whereas CLK levels decrease and PER and TIM accumulation are delayed when nmo is overexpressed in clock cells. These data suggest that nmo slows the pace of the circadian oscillator by altering CLK, PER, and TIM expression, thereby contributing to the generation of an ~24 hr circadian period.
authors.affiliation: Department of Biology and The Center for Biological Clocks Research, Texas A&M University, College Station, TX 77845-3258, USA.
authors.forename: Wangjie
authors.initials: W
authors.lastname: Yu
authors.forename: Jerry H
authors.initials: JH
authors.lastname: Houl
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hardin
mesh_terms: D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D056926:CLOCK Proteins / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology*; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D056950:Period Circadian Proteins / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference
chemical_list: D056930:ARNTL Transcription Factors; C120526:Clk protein, Drosophila; D029721:Drosophila Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; C112805:cyc protein, Drosophila; C096445:tim protein, Drosophila; D056926:CLOCK Proteins; D020928:Mitogen-Activated Protein Kinases; C110707:nmo protein, Drosophila