A large-scale functional RNAi screen reveals a role for CK2 in the mammalian circadian clock
- Bert Maier,
- Sabrina Wendt,
- Jens T. Vanselow,1,
- Thomas Wallach,
- Silke Reischl,
- Stefanie Oehmke,
- Andreas Schlosser,2 and
- Achim Kramer,3
Abstract
Post-translational processes are essential for the generation and dynamics of mammalian circadian rhythms. In particular, phosphorylation of the key circadian protein PER2 precisely controls the period and phase of circadian oscillations. However, the mechanisms underlying that control are poorly understood. Here, we identified in a high-throughput RNAi-based genetic screen casein kinase 2 (CK2) as a PER2-phosphorylating kinase and novel component of the mammalian circadian clock. When CK2 subunits are silenced by RNAi or when CK2 activity is inhibited pharmacologically, circadian rhythms are disrupted. CK2 binds to PER2 in vivo, phosphorylates PER2 specifically at N-terminal residues in vitro, and supports normal nuclear PER2 accumulation. Mutation of CK2 phosphorylation sites decreases PER2 stability and copies CK2 inhibition regarding oscillation dynamics. We propose a new concept of how PER2 phosphorylation and stabilization can set the clock speed in opposite directions, dependent on the phase of action.
Keywords
Footnotes
-
↵1 Present addresses: Center for Experimental Bioinformatics, University of Southern Denmark Campusvej 55, 5230 Odense M, Denmark;
-
↵2 Zentrum für Biosystemanalyse, Albert-Ludwigs-Universität Freiburg, Habsburgerstr. 49, 79104 Freiburg, Germany
-
↵3 Corresponding author.
↵E-MAIL achim.kramer{at}charite.de; FAX 49-30-450-524942.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.512209.
-
Supplemental material is available at http://www.genesdev.org.
-
- Received October 31, 2008.
- Accepted February 10, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press
