Role of phosphorylation in the mammalian circadian clock

Cold Spring Harb Symp Quant Biol. 2007;72:167-76. doi: 10.1101/sqb.2007.72.036.


Circadian clocks regulate a wide variety of processes ranging from gene expression to behavior. At the molecular level, circadian rhythms are thought to be produced by a set of clock genes and proteins interconnected to form transcriptional-translational feedback loops. Rhythmic gene expression was formerly regarded as the major drive for rhythms in clock protein abundance, but recent findings underline the crucial importance of posttranslational mechanisms for both the generation and dynamics of circadian rhythms. In particular, the reversible phosphorylation of PER proteins-essential components within the negative feedback loop in Drosophila and mammals-seems to have a key role for the correct timing of nuclear repression. To understand how PER protein phosphorylation regulates the dynamics of the circadian oscillator, we have mapped endogenous phosphorylation sites in mPER2. Detailed investigation of the functional role of one particular phosphorylation site (Ser-659, which is mutated in the familial advanced sleep phase syndrome [FASPS]) led us propose a model of functionally different phosphorylation sites in PER2. This concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • CLOCK Proteins
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology*
  • Feedback, Physiological
  • Humans
  • Mammals
  • Mice
  • Models, Biological
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Period Circadian Proteins
  • Phenotype
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein Processing, Post-Translational
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • Transcription Factors / genetics
  • Transcription Factors / physiology


  • Cell Cycle Proteins
  • Nuclear Proteins
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Trans-Activators
  • Transcription Factors
  • CLOCK Proteins
  • CLOCK protein, human
  • Clock protein, mouse
  • Protein Kinases
  • Phosphoprotein Phosphatases