The molecular ticks of the Drosophila circadian clock

• The Drosophila circadian pacemaker consists of transcriptional feedback loops.
• Cascades of protein phosphorylation/dephosphorylation determine period length.
• Specific ubiquitin ligases and proteases regulate circadian protein stability and activity.
• mRNA stability and translation control emerge as key circadian regulatory mechanisms.

Drosophila is a powerful model to understand the mechanisms underlying circadian rhythms. The Drosophila molecular clock is comprised of transcriptional feedback loops. The expressions of the critical transcriptional activator CLK and its repressors PER and TIM are under tight transcriptional control. However, posttranslational modification of these proteins and regulation of their stability are critical to their function and to the generation of 24-h period rhythms. We review here recent progress made in our understanding of PER, TIM and CLK posttranslational control. We also review recent studies that are uncovering the importance of novel regulatory mechanisms that affect mRNA stability and translation of circadian pacemaker proteins and their output.