Protein phosphatase 4 controls circadian clock dynamics by modulating CLOCK/BMAL1 activity

Sabrina Klemz, Thomas Wallach, Sandra Korge, Mechthild Rosing, Roman Klemz, Bert Maier, Nicholas C. Fiorenza, Irem Kaymak, Anna K. Fritzsche, Erik D. Herzog, Ralf Stanewsky, Achim Kramer

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mammals and Drosophila. Genetic depletion of PPP4 shortens the circadian period, whereas overexpression lengthens it. PPP4 inhibits CLOCK/BMAL1 transactivation activity by binding to BMAL1 and counteracting its phosphorylation. This leads to increased CLOCK/BMAL1DNA occupancy and decreased transcriptional activity, which counteracts the "kamikaze" properties of CLOCK/BMAL1. Through this mechanism, PPP4 contributes to the critical delay of negative feedback by retarding PER/CRY/CK1δ- mediated inhibition of CLOCK/BMAL1.

Original languageEnglish
Pages (from-to)1161-1174
Number of pages14
JournalGenes and Development
Issue number15-16
StatePublished - Aug 1 2021


  • BMAL1
  • Circadian clock
  • Circadian rhythm
  • Phosphorylation
  • Protein phosphatase 4


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