Format

Send to

Choose Destination
Nat Genet. 2006 Mar;38(3):312-9. Epub 2006 Feb 12.

Feedback repression is required for mammalian circadian clock function.

Author information

1
Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Dr., San Diego, California 92121, USA.

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.

PMID:
16474406
PMCID:
PMC1994933
DOI:
10.1038/ng1745
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center