| First Author | Fustin JM | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 23 | Pages | 5980-5985 |
| PubMed ID | 29784786 | Mgi Jnum | J:263005 |
| Mgi Id | MGI:6161006 | Doi | 10.1073/pnas.1721371115 |
| Citation | Fustin JM, et al. (2018) Two Ck1delta transcripts regulated by m6A methylation code for two antagonistic kinases in the control of the circadian clock. Proc Natl Acad Sci U S A 115(23):5980-5985 |
| abstractText | The N(6)-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 (Ck1delta), coding for a critical kinase in the control of circadian rhythms, cellular growth, and survival, is negatively regulated by m6A. Inhibition of Ck1delta mRNA methylation leads to increased translation of two alternatively spliced CK1delta isoforms, CK1delta1 and CK1delta2, uncharacterized until now. The expression ratio between these isoforms is tissue-specific, CK1delta1 and CK1delta2 have different kinase activities, and they cooperate in the phosphorylation of the circadian clock protein PER2. While CK1delta1 accelerates the circadian clock by promoting the decay of PER2 proteins, CK1delta2 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 CK1delta, the existence of two isoforms calls for a re-evaluation of past research when CK1delta1 and CK1delta2 were simply CK1delta. |
