Abstract
Circadian rhythms, endogenous cycles of about 24 h in physiology, are generated by a master clock located in the suprachiasmatic nucleus of the hypothalamus and other clocks located in the brain and peripheral tissues. Circadian disruption is known to increase the incidence of various illnesses, such as mental disorders, metabolic syndrome, and cancer. At the molecular level, periodicity is established by a set of clock genes via autoregulatory translation–transcription feedback loops. This clock mechanism is regulated by post-translational modifications such as phosphorylation and ubiquitination, which set the pace of the clock. Ubiquitination in particular has been found to regulate the stability of core clock components but also other clock protein functions. Mutation of genes encoding ubiquitin ligases can cause either elongation or shortening of the endogenous circadian period. Recent research has also started to uncover roles for deubiquitination in the molecular clockwork. Here, we review the role of the ubiquitin pathway in regulating the circadian clock and we propose that ubiquitination is a key element in a clock protein modification code that orchestrates clock mechanisms and circadian behavior over the daily cycle.
Highlights
THE MOLECULAR CIRCADIAN CLOCK Circadian rhythms are endogenous ∼24 h cycles in physiology and behavior generated by a master clock in the suprachiasmatic nucleus of the hypothalamus, and clocks located in most other tissues
Hundreds of clock-controlled genes, which do not participate in the clock mechanism, but whose transcription is under the control of the clock molecular machinery, present rhythms at the RNA and protein levels (Storch et al, 2002; Yan et al, 2008), linking the circadian clock with cellular physiology
Given that different modifications often converge on the same clock protein, we propose the existence of a clock protein modification code whereby the fate/function of a given protein is determined by the precise combination and/or the consecutive occurrence of different posttranslational modifications (PTMs)
Summary
THE MOLECULAR CIRCADIAN CLOCK Circadian rhythms are endogenous ∼24 h cycles in physiology and behavior generated by a master clock in the suprachiasmatic nucleus of the hypothalamus, and clocks located in most other tissues. Elongated free-running period of locomotor activity rhythms; altered response to light; altered clock gene expression and increased levels of ubiquitinated PER1 in fibroblasts; no change in PER1 stability; alteration in the timing of PER1 intracellular localization. USP2 may mediate the response of the clock to inflammation, as the expression of the gene is increased in response to TNFα treatment, and CRY1 protein induction in response to this cytokine is abrogated when Usp expression is knocked down (Tong et al, 2012) Together, these studies ascribe a pivotal role to USP2, and deubiquitination in general, in the circadian clock mechanism, and as an integrator of environmental and physiological signals, and in output pathways linking the molecular clockwork to cellular and physiological functions. Combinations of different phosphorylation events can regulate protein fate differentially: for example, in Drosophila, PER phosphorylation by DBT is modulated by prior action of another kinase, NEMO, and these kinases have opposing effects on PER stability (Chiu et al, 2011)
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