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Cell Metab. 2013 Feb 5;17(2):291-302. doi: 10.1016/j.cmet.2012.12.017.

Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock.

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1
Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA.

Abstract

Posttranslational modifications play central roles in myriad biological pathways including circadian regulation. We employed a circadian proteomic approach to demonstrate that circadian timing of phosphorylation is a critical factor in regulating complex GSK3β-dependent pathways and identified O-GlcNAc transferase (OGT) as a substrate of GSK3β. Interestingly, OGT activity is regulated by GSK3β; hence, OGT and GSK3β exhibit reciprocal regulation. Modulating O-GlcNAcylation levels alter circadian period length in both mice and Drosophila; conversely, protein O-GlcNAcylation is circadianly regulated. Central clock proteins, Clock and Period, are reversibly modified by O-GlcNAcylation to regulate their transcriptional activities. In addition, O-GlcNAcylation of a region in PER2 known to regulate human sleep phase (S662-S674) competes with phosphorylation of this region, and this interplay is at least partly mediated by glucose levels. Together, these results indicate that O-GlcNAcylation serves as a metabolic sensor for clock regulation and works coordinately with phosphorylation to fine-tune circadian clock.

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PMID:
23395175
PMCID:
PMC3597447
DOI:
10.1016/j.cmet.2012.12.017
[Indexed for MEDLINE]
Free PMC Article

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