Role of posttranscriptional regulation in circadian clocks: lessons from Drosophila.

Incredible progress has been made in the last few years in our understanding of the molecular mechanisms underlying circadian clocks. Many of the recent insights have been gained by the isolation and characterization of novel clock mutants and their associated gene products. As might be expected based on theoretical considerations and earlier studies that indicated the importance of temporally regulated macromolecular synthesis for the manifestation of overt rhythms, daily oscillations in the levels of "clock" RNAs and proteins are a pervasive feature of these timekeeping devices. How are these molecular rhythms generated and synchronized? Recent evidence accumulated from a wide variety of model organisms, ranging from bacteria to mammals, points toward an emerging trend; at the "heart" of circadian oscillators lies a cell autonomous transcriptional feedback loop that is composed of alternatively functioning positive and negative elements. Nonetheless, it is also clear that to bring this transcriptional feedback loop to "life" requires important contributions from posttranscriptional regulatory schemes. For one thing, there must be times in the day when the activities of negative-feedback regulators are separated from the activities of the positive regulators they act on, or else the oscillatory potential of the system will be dissipated, resulting in a collection of molecules at steady state. This review mainly summarizes the role of posttranscriptional regulation in the Drosophila melanogaster time-keeping mechanism. Accumulating evidence from Drosophila and other systems suggests that posttranscriptional regulatory mechanisms increase the dynamic range of circadian transcriptional feedback loops, overlaying them with appropriately timed biochemical constraints that not only engender these loops with precise daily periods of about 24 h, but also with the ability to integrate and respond rapidly to multiple environmental cues such that their phases are aligned optimally to the prevailing external conditions.