Feedback Repression is Required for Mammalian Circadian Clock Function

Overview

Journal Nat Genet

Specialty Genetics

Date 2006 Feb 14

PMID 16474406

Citations 166

Authors

Trey K Sato

Rikuhiro G Yamada

Hideki Ukai

Julie E Baggs

Loren J Miraglia

Tetsuya J Kobayashi

David K Welsh

Steve A Kay

Hiroki R Ueda

John B Hogenesch

Affiliations

Soon will be listed here.

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.

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