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

Sabrina Klemz1, Thomas Wallach1, Sandra Korge1

  • 1Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin,10117 Berlin, Germany.

Genes & Development
|July 24, 2021
PubMed
Summary

Protein phosphatase 4 (PPP4) regulates circadian rhythms by inhibiting CLOCK/BMAL1 activity. This phosphatase delays negative feedback, ensuring proper circadian clock function in mammals and Drosophila.

Keywords:
BMAL1CLOCKcircadian clockcircadian rhythmphosphorylationprotein phosphatase 4

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Area of Science:

  • Chronobiology
  • Molecular Biology
  • Biochemistry

Background:

  • Circadian rhythms are governed by post-translational modifications of clock proteins, primarily phosphorylation.
  • While kinases are well-studied, the role of phosphatases in circadian regulation remains largely unknown.

Purpose of the Study:

  • To investigate the role of phosphatases in circadian clock function.
  • To identify specific phosphatases involved in regulating circadian rhythms.

Main Methods:

  • Systematic RNA interference (RNAi) screen in human cells.
  • Functional analysis of identified phosphatases in mammalian and Drosophila circadian systems.

Main Results:

  • Protein phosphatase 4 (PPP4) and its regulatory subunit PPP4R2 were identified as critical circadian components.
  • Depletion of PPP4 shortened the circadian period; overexpression lengthened it.
  • PPP4 inhibits CLOCK/BMAL1 transactivation by binding to BMAL1, counteracting its phosphorylation, increasing DNA occupancy, and decreasing transcriptional activity.

Conclusions:

  • PPP4 plays a crucial role in regulating circadian rhythm dynamics.
  • PPP4 delays negative feedback by modulating CLOCK/BMAL1 activity, thereby fine-tuning the circadian clock.