Two Ck1δ transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock.
Two Ck1δ transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock.
复制标题
DOI：
10.1073/pnas.1721371115
复制
发表时间：
2018-06-05
影响因子：
11.1
通讯作者：
Okamura H
中科院分区：
文献类型：
--
作者：
Fustin JM;Kojima R;Itoh K;Chang HY;Ye S;Zhuang B;Oji A;Gibo S;Narasimamurthy R;Virshup D;Kurosawa G;Doi M;Manabe I;Ishihama Y;Ikawa M;Okamura H
信使核糖核酸（mRNA）中最丰富的修饰是内部腺苷的N6 -甲基化（m6A），但对于大多数mRNA来说，m6A的生理功能尚不清楚。在此我们表明，编码控制昼夜节律的关键激酶的酪蛋白激酶1δ mRNA（Ck1δ）受m6A调控。当m6A被抑制时，由于翻译增强，两种迄今尚未明确特征的CK1δ异构体的表达增加。CK1δ的这种增加导致生物钟变慢，因为生物钟蛋白PER2在一个关键残基上的磷酸化增加，从而导致PER2蛋白的稳定。
mRNA中内部腺苷的N6 -甲基化（m6A）已在整个转录组中进行了定量和定位。然而，在大多数高度甲基化的mRNA中，m6A的生理意义尚不清楚。先前已证明，基于转录 - 翻译负反馈回路的生物钟对m6A的普遍抑制敏感。在此，我们表明，编码控制昼夜节律、细胞生长和存活的关键激酶的酪蛋白激酶1δ mRNA（Ck1δ）受m6A负调控。抑制Ck1δ mRNA的甲基化导致两种可变剪接的CK1δ异构体CK1δ1和CK1δ2的翻译增加，这两种异构体此前尚未明确特征。这些异构体之间的表达比例具有组织特异性，CK1δ1和CK1δ2具有不同的激酶活性，并且它们在生物钟蛋白PER2的磷酸化过程中协同作用。CK1δ1通过促进PER2蛋白的降解来加速生物钟，而CK1δ2通过在PER2蛋白的一个关键残基上增加磷酸化来稳定PER2，从而使生物钟变慢。这些观察结果对先前建立的PER2磷酸化模型提出了挑战，并且鉴于CK1δ的多种功能和作用靶点，两种异构体的存在要求对过去将CK1δ1和CK1δ2简单视为CK1δ的研究进行重新评估。
The most abundant modification in mRNA is the N6-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. 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.
登录
查看更多内容
影响因子：
4.2
作者：
Ishida, Y;Yagita, K;Okamura, H
通讯作者：
Okamura, H
影响因子：
4.8
作者：
Shanware, Naval P.;Hutchinson, John A.;Tibbetts, Randal S.
通讯作者：
Tibbetts, Randal S.
影响因子：
10.5
作者：
Ke S;Alemu EA;Mertens C;Gantman EC;Fak JJ;Mele A;Haripal B;Zucker-Scharff I;Moore MJ;Park CY;Vågbø CB;Kusśnierczyk A;Klungland A;Darnell JE Jr;Darnell RB
通讯作者：
Darnell RB
影响因子：
64.5
作者：
Price, JL;Blau, J;Young, MW
通讯作者：
Young, MW
影响因子：
7.4
作者：
Schlosser, A;Vanselow, JT;Kramer, A
通讯作者：
Kramer, A