Circadian clocks are internal timing systems that enable organisms to adjust their behavioral and physiological rhythms to the daily changes of their environment. These clocks generate self‐sustained oscillations at the cellular, tissue, and behavioral level. The rhythm‐generating mechanism is based on a gene expression network with a delayed negative feedback loop that causes the transcripts to oscillate with a period of approximately 24 hr. This oscillatory nature of the proteins involved in this network necessitates that they are intrinsically unstable, with a short half‐life. Hence, post‐translational modifications (PTMs) are important to precisely time the presence, absence, and interactions of these proteins at appropriate times of the day. Ubiquitination and deubiquitination are counter‐balancing PTMs which play a key role in this regulatory process. In this review, we take a comprehensive look at the roles played by the processes of ubiquitination and deubiquitination in the clock machinery of the most commonly studied eukaryotic models of the circadian clock: plants, fungi, fruit flies, and mammals. We present the effects exerted by ubiquitinating and deubiquitinating enzymes on the stability, but also the activity, localization, and interactions of clock proteins. Overall, these PTMs have key roles in regulating not only the pace of the circadian clocks but also their response to external cues and their control of cellular functions.

Ubiquitin specific peptidase 2 (USP2) is a deubiquitinating enzyme expressed almost ubiquitously in the body, including in multiple brain regions. We previously showed that mice lacking USP2 present altered locomotor activity rhythms and response of the clock to light. However, the possible implication of USP2 in regulating other behaviors has yet to be tested. To address this, we ran a battery of behavioral tests on Usp2   KO mice. Firstly, we confirmed our prior findings of increased daily activity and reduced activity fragmentation in Usp2 KO mice. Further, mice lacking USP2 showed impaired motor coordination and equilibrium, a decrease in anxiety-like behavior, a deficit in short-term recognition memory and in sensorimotor gating. On the other hand, no effects of Usp2 gene deletion were found on spatial memory. Hence, our data uncover the implication of USP2 in different behaviors and expands the range of the known functions of this deubiquitinase.

Mistimed exposure to light has been demonstrated to negatively affect multiple aspects of physiology and behavior. Here we analyzed the effects of chronic exposure to abnormal lighting conditions in mice. We exposed mice for 1 year to either: a standard light/dark cycle, a “light-pollution” condition in which low levels of light were present in the dark phase of the circadian cycle (dim light at night, DLAN), or altered light cycles in which the length of the weekday and weekend light phase differed by 6 h (“social jetlag”). Mice exhibited several circadian activity phenotypes, as well as changes in motor function, associated particularly with the DLAN condition. Our data suggest that these phenotypes might be due to changes outside the core clock. Dendritic spine changes in other brain regions raise the possibility that these phenotypes are mediated by changes in neuronal coordination outside of the clock. Given the prevalence of artificial light exposure in the modern world, further work is required to establish whether these negative effects are observed in humans as well.

Ubiquitin specific peptidase 2 (USP2) is a deubiquitinating enzyme expressed almost ubiquitously in the body, including in multiple brain regions. We previously showed that mice lacking USP2 present altered locomotor activity rhythms and response of the clock to light. However, the possible implication of USP2 in regulating other behaviors has yet to be tested. To address this, we ran a battery of behavioral tests on Usp2 KO mice. Firstly, we confirmed our prior findings of increased daily activity and reduced activity fragmentation in Usp2 KO mice. Further, mice lacking USP2 showed impaired motor coordination and equilibrium, a decrease in anxiety-like behavior, a deficit in working memory and in sensorimotor gating. On the other hand, no effects of Usp2 gene deletion were found on spatial memory. Hence, our data uncover the implication of USP2 in different behaviors and expands the range of the known functions of this deubiquitinase.

All living organisms experience daily environmental cycles and have consequently evolved to synchronize and adapt to this changing environment. Biological processes such as hormonal secretion, body temperature and sleep follow daily cycles called circadian rhythms that are driven by a molecular clock running in most cells and tissues of the body. This clock is composed of transcriptional-translational negative feedback loops involving clock genes and proteins. This molecular mechanism functions with a period of ~24 hours, and it promotes daily rhythms in the expression of numerous genes. For this robust mechanism to function, the abundance and activity of clock proteins need to be tightly regulated. One of the mechanisms by which this can be achieved is ubiquitination. Indeed, many ubiquitin ligases can tag core clock proteins in order to target them for proteasomal degradation. However, deubiquitinases can reverse this process by removing or modifying these ubiquitin signals and are thus important enzymes in clock protein homeostasis and regulation. Recent studies on the mammalian and Drosophila clock mechanisms have identified a number of deubiquitinases able to stabilize core clock proteins, change their cellular localization or even regulate their activity. In this review, we aim to discuss the fundamental roles of ubiquitination and deubiquitination in the circadian clock by presenting all deubiquitinases found to be involved in circadian rhythms in the aim to give a global view of recent advances in this emerging field.