A large-scale functional RNAi screen reveals a role for CK2 in the mammalian circadian clock.
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.
Maier
Bert
B
Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Wendt
Sabrina
S
Vanselow
Jens T
JT
Wallach
Thomas
T
Reischl
Silke
S
Oehmke
Stefanie
S
Schlosser
Andreas
A
Kramer
Achim
A
D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002940:Circadian Rhythm / Q000502:physiology*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D056950:Period Circadian Proteins; D010766:Phosphorylation; D034622:RNA Interference / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C421902:PER2 protein, human; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D047390:Casein Kinase II