Cyclin dependent kinase 5 (CDK5) regulates the circadian clock
- University of Fribourg, Switzerland
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.
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Data from: Cyclin dependent kinase 5 (CDK5) regulates the circadian clockDryad Digital Repository, doi:10.5061/dryad.4067r78.
Article and author information
Author details
Jürgen A Ripperger
Elisabetta Cameroni
Claudio De Virgilio
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.
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).
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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