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Feedback repression is required for mammalian circadian clock function.

ABSTRACT: 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.

SUBMITTER: Sato TK

PROVIDER: S-EPMC1994933 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Feedback repression is required for mammalian circadian clock function.

Sato Trey K TK Yamada Rikuhiro G RG Ukai Hideki H Baggs Julie E JE Miraglia Loren J LJ Kobayashi Tetsuya J TJ Welsh David K DK Kay Steve A SA Ueda Hiroki R HR Hogenesch John B JB

Nature genetics 20060212 3

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 inter ...[more]

PMID: 16474406

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