Editing Circadian clock (section)

== Post-translational modification ==
The autoregulatory feedback loops in clocks take about 24 hours to complete a cycle and constitute a circadian molecular clock. This generation of the ~24-hour molecular clock is governed by [[post-translational modification]]s such as [[phosphorylation]], [[sumoylation]], [[histone acetylation]] and [[methylation]], and [[ubiquitination]].<ref name="Gallego"/> Reversible phosphorylation regulates important processes such as nuclear entry, formation of protein complexes and [[protein degradation]]. Each of these processes significantly contributes to keeping the period at ~24 hours and lends the precision of a circadian clock by affecting the stability of the 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.<ref name="Ko"/>

Proteins responsible for post-translational modification of clock genes include [[casein kinase]] family members ([[CSNK1D|casein kinase 1 delta]] (CSNK1D) and [[CSNK1E|casein kinase 1 epsilon]] (CSNK1E) and the F-box [[FBXL3|leucine-rich repeat protein 3]] (FBXL3).<ref name="Gallego"/> In mammals, CSNK1E and CSNK1D are critical factors that regulate the core circadian protein turnover.<ref name="Ko"/> 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.<ref name="Ko"/> These [[mutations]] have become of particular interest in humans as they are implicated in the [[advanced sleep phase disorder]].<ref name="Gallego"/> A small ubiquitin-related modifier protein modification of BMAL1 has also been proposed as another level of post-translational regulation.<ref name="Ko"/>