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      Positional Syntenic Cloning and Functional Characterization of the Mammalian Circadian Mutation tau

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          Abstract

          The tau mutation is a semidominant autosomal allele that dramatically shortens period length of circadian rhythms in Syrian hamsters. We report the molecular identification of the tau locus using genetically directed representational difference analysis to define a region of conserved synteny in hamsters with both the mouse and human genomes. The tau locus is encoded by casein kinase I epsilon (CKIɛ), a homolog of the Drosophila circadian gene double-time . In vitro expression and functional studies of wild-type and tau mutant CKIɛ enzyme reveal that the mutant enzyme has a markedly reduced maximal velocity and autophosphorylation state. In addition, in vitro CKIɛ can interact with mammalian PERIOD proteins, and the mutant enzyme is deficient in its ability to phosphorylate PERIOD. We conclude that tau is an allele of hamster CKIɛ and propose a mechanism by which the mutation leads to the observed aberrant circadian phenotype in mutant animals.

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          Most cited references78

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          Role of the CLOCK protein in the mammalian circadian mechanism.

          The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and is related to transcription factors that act as heterodimers. Potential partners of CLOCK were isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1 at known circadian clock sites in brain and retina. CLOCK-BMAL1 heterodimers activated transcription from E-box elements, a type of transcription factor-binding site, found adjacent to the mouse per1 gene and from an identical E-box known to be important for per gene expression in Drosophila. Mutant CLOCK from the dominant-negative Clock allele and BMAL1 formed heterodimers that bound DNA but failed to activate transcription. Thus, CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.
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            Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels.

            Mutations in the period (per) gene of Drosophila melanogaster affect both circadian and ultradian rhythms. Levels of per gene product undergo circadian oscillation, and it is now shown that there is an underlying oscillation in the level of per RNA. The observations indicate that the cycling of per-encoded protein could result from per RNA cycling, and that there is a feedback loop through which the activity of per-encoded protein causes cycling of its own RNA.
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              Transplanted suprachiasmatic nucleus determines circadian period

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                Author and article information

                Journal
                Science
                Science
                American Association for the Advancement of Science (AAAS)
                0036-8075
                1095-9203
                April 21 2000
                April 21 2000
                : 288
                : 5465
                : 483-491
                Affiliations
                [1 ]Department of Neurobiology and Physiology,
                [2 ]Howard Hughes Medical Institute, Northwestern University, Evanston, IL 60208, USA.
                [3 ]Department of Biology, National Science Foundation Center for Biological Timing, University of Virginia, Charlottesville, VA 22903, USA.
                [4 ]Department of Psychology, University of Toronto, Toronto, Ontario M5S 3G3, Canada.
                Article
                10.1126/science.288.5465.483
                10775102
                7f13ca76-4f1c-4087-9ceb-8eace436a1c5
                © 2000
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