Abstract

Circadian oscillations emerge from transcriptional and post-translational feedback loops. An important step in generating rhythmicity is the translocation of clock components into the nucleus, which is regulated in many cases by kinases. In mammals, the kinase promoting the nuclear import of the key clock component Period 2 (PER2) is unknown. Here we show that the cyclin-dependent kinase 5 (CDK5) regulates the mammalian circadian clock involving phosphorylation of PER2. Knock-down of Cdk5 in the suprachiasmatic nuclei (SCN), the main coordinator site of the mammalian circadian system, shortened the free-running period in mice. CDK5 phosphorylated PER2 at serine residue 394 (S394) in a diurnal fashion. This phosphorylation facilitated interaction with Cryptochrome 1 (CRY1) and nuclear entry of the PER2-CRY1 complex. Taken together, we found that CDK5 drives nuclear entry of PER2, which is critical for establishing an adequate circadian period of the molecular circadian cycle. Of note is that CDK5 may not exclusively phosphorylate PER2, but in addition may regulate other proteins that are involved in the clock mechanism. Taken together, it appears that CDK5 is critically involved in the regulation of the circadian clock and may represent a link to various diseases affected by a derailed circadian clock.

Data availability

Data supporting the findings of this work are available within the paper and its Supplementary Information files. Non-commercial biological materials are provided upon request to the coresponding author. Proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD012068. The Per2Brdm1 mutant mouse strain is available at the Jackson Laboratory Stock No: 003819 (B6.Cg-Per2 tm1Brd Tyr c-Brd). The floxed Per2 mice are available at the European Mouse Mutant Archive (EMMA) strain ID EM:10599, B6;129P2-Per2tm1Ual/Biat.

The following data sets were generated

Article and author information

Author details

  1. Andrea Brenna

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8542-9855
  2. Iwona Olejniczak

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Rohit Chavan

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Jürgen A Ripperger

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9345-5172
  5. Sonja Langmesser

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Elisabetta Cameroni

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9102-8943
  7. Zehan Hu

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  8. Claudio De Virgilio

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8826-4323
  9. Jörn Dengjel

    Department of Biology, University of Fribourg, Friborug, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9453-4614
  10. Urs Albrecht

    Department of Biology, University of Fribourg, Fribourg, Switzerland
    For correspondence
    urs.albrecht@unifr.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0663-8676

Funding

Fondazione Cenci Bolognetti, Instituto Pasteur (NA)

  • Andrea Brenna

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_166682)

  • Urs Albrecht

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_166474/1)

  • Claudio De Virgilio

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (316030_177088)

  • Jörn Dengjel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Louis J Ptáček, University of California, San Francisco, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Swiss Legislation and the declaration of Helsinki. The protocols were approved by the state veterinarian of the State of Fribourg (Permit Number: 2015-33).

Version history

  1. Received: August 7, 2019
  2. Accepted: November 3, 2019
  3. Accepted Manuscript published: November 5, 2019 (version 1)
  4. Version of Record published: December 3, 2019 (version 2)

Copyright

© 2019, Brenna et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Andrea Brenna
  2. Iwona Olejniczak
  3. Rohit Chavan
  4. Jürgen A Ripperger
  5. Sonja Langmesser
  6. Elisabetta Cameroni
  7. Zehan Hu
  8. Claudio De Virgilio
  9. Jörn Dengjel
  10. Urs Albrecht
(2019)
Cyclin dependent kinase 5 (CDK5) regulates the circadian clock
eLife 8:e50925.
https://doi.org/10.7554/eLife.50925

Share this article

https://doi.org/10.7554/eLife.50925

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