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

Jean Michel Fustin, Rika Kojima, Kakeru Itoh, Hsin Yi Chang, Ye Shiqi, Bowen Zhuang, Asami Oji, Shingo Gibo, Rajesh Narasimamurthy, David Virshup, Gen Kurosawa, Masao Doi, Ichiro Manabe, Yasushi Ishihama, Masahito Ikawa, Hitoshi Okamura

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5980-5985
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number23
DOIs
Publication statusPublished - Jun 5 2018
Externally publishedYes

Keywords

  • Casein kinase
  • Circadian
  • M6A
  • Methylation
  • Splicing

ASJC Scopus subject areas

  • General

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  • Cite this

    Fustin, J. M., Kojima, R., Itoh, K., Chang, H. Y., Shiqi, Y., Zhuang, B., Oji, A., Gibo, S., Narasimamurthy, R., Virshup, D., Kurosawa, G., Doi, M., Manabe, I., Ishihama, Y., Ikawa, M., & Okamura, H. (2018). Two Ck1δ transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock. Proceedings of the National Academy of Sciences of the United States of America, 115(23), 5980-5985. https://doi.org/10.1073/pnas.1721371115