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Proc Natl Acad Sci U S A. 2018 Jun 5;115(23):5980-5985. doi: 10.1073/pnas.1721371115. Epub 2018 May 21.

Two Ck1δ transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock.

Author information

1
Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, 606-8501 Kyoto, Japan; j.m.fustin@pharm.kyoto-u.ac.jp okamurah@pharm.kyoto-u.ac.jp.
2
Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, 606-8501 Kyoto, Japan.
3
Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 606-8501 Kyoto, Japan.
4
Animal Resource Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871 Osaka, Japan.
5
Theoretical Biology Laboratory, RIKEN, 351-0198 Wako, Japan.
6
Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857, Singapore.
7
Theoretical Biology Laboratory, Interdisciplinary Theoretical and Mathematical Sciences Program, RIKEN, 351-0198 Wako, Japan.
8
Department of Aging Research, Chiba University Graduate School of Medicine, 260-8670 Chiba, Japan.

Abstract

The N6-methylation of internal adenosines (m6A) in mRNA has been quantified and localized throughout the transcriptome. However, the physiological significance of m6A in most highly methylated mRNAs is unknown. It was demonstrated previously that the circadian clock, based on transcription-translation negative feedback loops, is sensitive to the general inhibition of m6A. Here, we show that the Casein Kinase 1 Delta mRNA (Ck1δ), coding for a critical kinase in the control of circadian rhythms, cellular growth, and survival, is negatively regulated by m6A. Inhibition of Ck1δ mRNA methylation leads to increased translation of two alternatively spliced CK1δ isoforms, CK1δ1 and CK1δ2, uncharacterized until now. The expression ratio between these isoforms is tissue-specific, CK1δ1 and CK1δ2 have different kinase activities, and they cooperate in the phosphorylation of the circadian clock protein PER2. While CK1δ1 accelerates the circadian clock by promoting the decay of PER2 proteins, CK1δ2 slows it down by stabilizing PER2 via increased phosphorylation at a key residue on PER2 protein. These observations challenge the previously established model of PER2 phosphorylation and, given the multiple functions and targets of CK1δ, the existence of two isoforms calls for a re-evaluation of past research when CK1δ1 and CK1δ2 were simply CK1δ.

KEYWORDS:

casein kinase; circadian; m6A; methylation; splicing

PMID:
29784786
PMCID:
PMC6003373
DOI:
10.1073/pnas.1721371115
[Indexed for MEDLINE]
Free PMC Article

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