REVIEW article
Front. Neurosci.
Sec. Sleep and Circadian Rhythms
Volume 19 - 2025 | doi: 10.3389/fnins.2025.1632905
This article is part of the Research TopicThe Neurogenetics of Circadian Rhythms: Implications for Health and DiseaseView all 5 articles
The Ubiquitin-Proteasome System in Circadian Regulation
Provisionally accepted
- Wayne State University, Detroit, United States
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To align sleep-wake behavior and internal physiology with the Earth's 24-hour light-dark cycle, organisms rely on circadian clocks-endogenous timekeeping systems that anticipate and adapt to daily environmental changes. These clocks are governed by transcription-translation feedback loops that produce rhythmic oscillations in gene expression, including key regulators such as PERIOD and CRYPTOCHROME. The timing and stability of these proteins are tightly controlled by posttranslational mechanisms, including ubiquitin-mediated degradation. The ubiquitin-proteasome system (UPS) ensures that clock proteins are cleared at precise times within the circadian cycle, a process which is essential for resetting the molecular clock and sustaining robust circadian rhythms.Disruption of this process can have profound impacts on human health and contribute to impairments in sleep timing, circadian phase, and rhythm amplitude. In this review, we focus on the mechanistic role of the UPS in circadian clock regulation, summarize key E3 ligases and deubiquitinating enzymes implicated in clock protein turnover, and highlight the essential role of the UPS on sleep timing and overall circadian biological homeostasis.
Keywords: Ubiquitination, deubiquitination, Transcriptional regulation, molecular clock, Protein homeostasis
Received: 22 May 2025; Accepted: 28 Jul 2025.
Copyright: © 2025 Costanzo, Prifti, Todi and Mohan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Ryan D Mohan, Wayne State University, Detroit, United States
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