Fustin, J.-M., Kojima, R., Itoh, K., Chang, H.-Y., Shiqi, Y., Zhuang, B., . . . 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. doi:10.1073/pnas.172137111

Chang, HY

Doi, M

Fustin, JM

Gibo, S

Ikawa, Masahito

Ishihama, Yasushi

Itoh, K

Kojima, Rika

Kurosawa, Gen

Manabe, Ichiro

Narasimamurthy, R

Oji, A

Okamura, Hitoshi

Shiqi, Y

Virshup, D

Zhuang, B

Proceedings of the National Academy of Sciences

English

体内リズムの24時間周期を決めるタンパク質を発見 --家族性睡眠相前進症候群(FASPS)の分子機構の解明--. 京都大学プレスリリース. 2018-05-23.This article has a Correction. Please see: Correction for Fustin et al., Two Ck1δ transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock  https://doi.org/10.1073/pnas.1809838115The 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

Fustin, Jean-Michel

Itoh, Kakeru

Chang, Hsin-Yi

Shiqi, Ye

Zhuang, Bowen

Oji, Asami

Gibo, Shingo

Narasimamurthy, Rajesh

Virshup, David

Doi, Masao

Kyoto University Research Information Repository

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

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.Fustin, J.-M., Kojima, R., Itoh, K., Chang, H.-Y., Shiqi, Y., Zhuang, B., . . . 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. doi:10.1073/pnas.172137111

Fustin, Jean Michel

Chang, Hsin Yi

Osaka University Knowledge Archive

Significance
          
            The most abundant modification in mRNA is the
            N
            6
            -methylation of internal adenosines (m6A), but m6A’s physiological function is unknown for most mRNAs. Here we show that Casein Kinase 1 Delta mRNA (
            Ck1δ
            ), coding for a critical kinase in the control of circadian rhythms, is regulated by m6A. When m6A is inhibited, the expression of two CK1δ isoforms, uncharacterized until now, increases due to enhanced translation. This increase in CK1δs leads to a slower clock because of increased phosphorylation of the clock protein PER2 at a key residue, leading to the stabilization of PER2 protein.
          </jats:p

Jean-Michel Fustin

Rika Kojima

Kakeru Itoh

Hsin-Yi Chang

Shiqi Ye

Bowen Zhuang

Asami Oji

Shingo Gibo

Rajesh Narasimamurthy

David Virshup

Gen Kurosawa

Masao Doi

Ichiro Manabe

Yasushi Ishihama

Masahito Ikawa

Hitoshi Okamura

Crossref

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

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

The University of Manchester - Institutional Repository

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

https://pure.manchester.ac.uk/ws/files/205995704/PNAS_2018_Fustin.pdf

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

Abstract

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Kyoto University Research Information Repository

Osaka University Knowledge Archive

Crossref

The University of Manchester - Institutional Repository