A role for O-GlcNAcylation in setting circadian clock speed
Kim, Eun Young; Jeong, Eun Hee; Park, Sujin; Jeong, Hyun-Jeong; Edery, Isaac; Cho, Jin Won
Institute for Medical Sciences, Ajou University School of Medicine
Posttranslational modifications of one or more central ‘clock’ proteins, most notably time-of-day dependent changes in phosphorylation, are critical for setting the pace of circadian (24 hr) clocks. In animals, PERIOD (PER) proteins are the key state-variable regulating circadian clock speed and undergo daily changes in abundance and cytoplasmic-nuclear distribution that are driven by a complex phosphorylation program. Here, we identify a novel post-translational modification in circadian regulation, O-GlcNAcylation that also contributes to setting clock speed. Knockdown or overexpression of Drosophila O-GlcNAc transferase (ogt) in clock cells either shortens or lengthens circadian behavioral rhythms, respectively. The Drosophila PER protein (dPER) is a direct target of OGT and undergoes daily changes in O-GlcNAcylation, a modification that is observed during the first half of the night when dPER is mainly localized to the cytoplasm. Intriguingly, the timing of when dPER translocates from the cytoplasm to the nucleus is advanced or delayed in flies wherein ogt expression is reduced or increased, respectively. Our results suggest that O-GlcNAcylation of dPER contributes to setting the correct pace of the clock by delaying the timing of dPER nuclear entry. In addition, OGT stabilizes dPER, suggesting that O-GlcNAcylation has multiple roles in circadian timing systems.
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