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Circadian clocks evolved to enable organisms to anticipate and prepare for periodic environmental changes driven by the day–night cycle. This internal timekeeping mechanism is built on autoregulatory transcription–translation feedback loops that control the rhythmic expression of core clock genes and their protein products. The levels of clock proteins rise and ebb throughout a 24-h period through their rhythmic synthesis and destruction. In the ubiquitin–proteasome system, the process of polyubiquitination, or the covalent attachment of a ubiquitin chain, marks a protein for degradation by the 26S proteasome. The process is regulated by E3 ubiquitin ligases, which recognize specific substrates for ubiquitination. In this review, we summarize the roles that known E3 ubiquitin ligases play in the circadian clocks of two popular model organisms: mice and fruit flies. We also discuss emerging evidence that implicates the N-degron pathway, an alternative proteolytic system, in the regulation of circadian rhythms. We conclude the review with our perspectives on the potential for the proteolytic and non-proteolytic functions of E3 ubiquitin ligases within the circadian clock system. [ABSTRACT FROM AUTHOR]

The central pacemakers of circadian timekeeping systems are highly robust yet adaptable, providing the temporal coordination of rhythms in behavior and physiological processes in accordance with the demands imposed by environmental cycles. These features of the central pacemaker are achieved by a multi-oscillator network in which individual cellular oscillators are tightly coupled to the environmental day-night cycle, and to one another via intercellular coupling. In this review, we will summarize the roles of various neurotransmitters and neuropeptides in the regulation of circadian entrainment and synchrony within the mammalian and Drosophila central pacemakers. We will also describe the diverse functions of protein kinases in the relay of input signals to the core oscillator or the direct regulation of the molecular clock machinery. [ABSTRACT FROM AUTHOR]