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. We also discuss emerging evidence that implicates the N-degron pathway, an alternative proteolytic system, in the regulation of circadian rhythms.
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. The process is regulated by E3 ubiquitin ligases, which recognize specific substrates for ubiquitination. 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 levels of clock proteins rise and ebb throughout a 24-h period through their rhythmic synthesis and destruction. 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. Circadian clocks evolved to enable organisms to anticipate and prepare for periodic environmental changes driven by the day–night cycle.
