The molecular ticks of the Drosophila circadian clock

Abstract

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-hr 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.

Figure 1

Conceptual schematic of the Drosophila circadian molecular clock. Heterodimeric transcription factor complex CLK/CYC drives the expression of many clock-controlled genes (ccgs). Among them, per and tim encode critical transcriptional repressors of CLK/CYC. This core feedback mechanism is tightly regulated at the transcriptional, post-transcriptional and posttranslational levels to introduce delays and checks to ensure a ~24 hr cycle. This figure emphasizes transcriptional and post-translational mechanisms. Arrows (→) indicate positive/enhanced regulation, while blunt-ends (┤) indicate negative/inhibitory regulation. CWO appears to be able to function either as a repressor or an activator [66]. Protein degradation is depicted with dashed lines.

Figure 2

Translational control mechanisms in the Drosophila circadian molecular clock. The microRNAs bantam and let7 regulate CLK and CWO expression, respectively. miR959–964, which regulates feeding and immunity, also have a mild effect on the period of circadian behavior rhythms and thus the molecular clock of circadian neurons. The mechanism is not yet known (dotted line). This miRNA cluster and let7 are under circadian control. ATX2/TYF promote specifically PER translation in circadian neurons by binding to per mRNA.