title: Clockwork Orange is a transcriptional repressor and a new Drosophila circadian pacemaker component.
abstract: Many organisms use circadian clocks to keep temporal order and anticipate daily environmental changes. In Drosophila, the master clock gene Clock promotes the transcription of several key target genes. Two of these gene products, PER and TIM, repress CLK-CYC-mediated transcription. To recognize additional direct CLK target genes, we designed a genome-wide approach and identified clockwork orange (cwo) as a new core clock component. cwo encodes a transcriptional repressor that synergizes with PER and inhibits CLK-mediated activation. Consistent with this function, the mRNA profiles of CLK direct target genes in cwo mutant flies manifest high trough values and low amplitude oscillations. Because behavioral rhythmicity fails to persist in constant darkness (DD) with little or no effect on average mRNA levels in flies lacking cwo, transcriptional oscillation amplitude appears to be linked to rhythmicity. Moreover, the mutant flies are long period, consistent with the late repression indicated by the RNA profiles. These findings suggest that CWO acts preferentially in the late night to help terminate CLK-CYC-mediated transcription of direct target genes including cwo itself. The presence of mammalian homologs with circadian expression features (Dec1 and Dec2) suggests that a similar feedback mechanism exists in mammalian clocks.
authors.affiliation: Department of Biology, Brandeis University, Waltham, MA 02454, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kadener
authors.forename: Dan
authors.initials: D
authors.lastname: Stoleru
authors.forename: Michael
authors.initials: M
authors.lastname: McDonald
authors.forename: Pipat
authors.initials: P
authors.lastname: Nawathean
authors.forename: Michael
authors.initials: M
authors.lastname: Rosbash
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001683:Biological Clocks / Q000235:genetics*; D056926:CLOCK Proteins; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D008954:Models, Biological; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology; D056950:Period Circadian Proteins; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C120526:Clk protein, Drosophila; C521952:Cwo protein, Drosophila; D029721:Drosophila Proteins; D009687:Nuclear Proteins; C539040:PER protein, Drosophila; D056950:Period Circadian Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D056926:CLOCK Proteins