Circadian Clock - Post-translational Modification

Post-translational Modification

The autoregulatory feedback loops in clocks take about 24 hour to complete a cycle and constitute a circadian molecular clock. This generation of the ~24-hour molecular clock is governed by post-translational modifications such as phosphorylation, sumolyation, histone acetylation and methylation, and ubiquitination. Reversible phosphorylation regulates important processes such as nuclear entry, formation of protein complexes and protein degradation. Each of these processes significantly contributes to the delay that keeps the period at ~24 hours and lends the precision of a circadian clock by affecting the stability of aforementioned core clock proteins. Thus, while transcriptional regulation generates rhythmic RNA levels, regulated posttranslational modifications control protein abundance, subcellular localization, and repressor activity of PER and CRY.

Proteins responsible for post-translational modification of clock genes include casein kinase I family members (CSNK1D and CSNK1E) and the F-box and leucine-rich repeat protein 3 (FBXL3). In mammals, Casein kinase 1 epsilon and Casein kinase 1 delta are critical factors that regulate the core circadian protein turnover. Experimental manipulation on either of these proteins results in dramatic effects on circadian periods, such as altered kinase activities and cause shorter circadian periods, and further demonstrates the importance of the post-translational regulation within the core mechanism of the circadian clock. These mutations have become of particular interest in humans as they are implicated in familial advanced sleep phase syndrome. A small ubiquitin-related modifier protein modification of BMAL1 has also been proposed as another level of post-translational regulation.