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Feedback repression is required for mammalian circadian clock function.

Sato, Trey and Yamada, Rikuhiro and Ukai, Hideki and Baggs, Julie and Miraglia, Loren and Kobayashi, Tetsuya J and Welsh, David K and Kay, Steve A and Ueda, Hiroki R and Hogenesch, John (2006) Feedback repression is required for mammalian circadian clock function. Nature Genetics, 38 (3). pp. 312-319. ISSN 1061-4036


Direct evidence for the requirement of transcriptional feedback repression in circadian clock function has been elusive. Here, we developed a molecular genetic screen in mammalian cells to identify mutants of the circadian transcriptional activators CLOCK and BMAL1, which were uncoupled from CRYPTOCHROME (CRY)-mediated transcriptional repression. Notably, mutations in the PER-ARNT-SIM domain of CLOCK and the C terminus of BMAL1 resulted in synergistic insensitivity through reduced physical interactions with CRY. Coexpression of these mutant proteins in cultured fibroblasts caused arrhythmic phenotypes in population and single-cell assays. These data demonstrate that CRY-mediated repression of the CLOCK/BMAL1 complex activity is required for maintenance of circadian rhythmicity and provide formal proof that transcriptional feedback is required for mammalian clock function.

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Date Deposited: 14 Dec 2009 14:04
Last Modified: 31 Jan 2013 01:25


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