Circadian Amplitude Regulation via FBXW7-Targeted REV-ERBα Degradation

Cell. 2016 Jun 16;165(7):1644-1657. doi: 10.1016/j.cell.2016.05.012. Epub 2016 May 26.


Defects in circadian rhythm influence physiology and behavior with implications for the treatment of sleep disorders, metabolic disease, and cancer. Although core regulatory components of clock rhythmicity have been defined, insight into the mechanisms underpinning amplitude is limited. Here, we show that REV-ERBα, a core inhibitory component of clock transcription, is targeted for ubiquitination and subsequent degradation by the F-box protein FBXW7. By relieving REV-ERBα-dependent repression, FBXW7 provides an unrecognized mechanism for enhancing the amplitude of clock gene transcription. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of REV-ERBα is necessary for FBXW7 recognition. Moreover, targeted hepatic disruption of FBXW7 alters circadian expression of core clock genes and perturbs whole-body lipid and glucose levels. This CDK1-FBXW7 pathway controlling REV-ERBα repression defines an unexpected molecular mechanism for re-engaging the positive transcriptional arm of the clock, as well as a potential route to manipulate clock amplitude via small molecule CDK1 inhibition.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Circadian Clocks
  • Circadian Rhythm*
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • F-Box-WD Repeat-Containing Protein 7
  • Gene Knockout Techniques
  • Humans
  • Lipid Metabolism
  • Liver / metabolism*
  • Mice
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Transcriptome
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Fbxw7 protein, mouse
  • NR1D1 protein, human
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Ubiquitin-Protein Ligases
  • CDC2 Protein Kinase