Edery I
Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA.
Chronobiol Int. 1999 Jul;16(4):377-414. doi: 10.3109/07420529908998716.
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.
在过去几年里，我们对生物钟分子机制的理解取得了惊人的进展。最近的许多见解是通过分离和鉴定新型生物钟突变体及其相关基因产物获得的。基于理论考量以及早期研究表明时间调控的大分子合成对于明显节律的表现至关重要，正如预期的那样，“生物钟”RNA和蛋白质水平的每日振荡是这些计时装置的一个普遍特征。这些分子节律是如何产生和同步的呢？最近从从细菌到哺乳动物等多种模式生物积累的证据指向了一个新趋势；昼夜节律振荡器的“核心”是一个细胞自主转录反馈环，它由交替发挥作用的正性和负性元件组成。尽管如此，很明显，要使这个转录反馈环“运转起来”，转录后调控机制也起着重要作用。一方面，一天中必须有这样的时刻，负反馈调节因子的活性与它们作用的正调节因子的活性分开，否则系统的振荡潜能将被耗散，导致分子处于稳态。这篇综述主要总结了转录后调控在果蝇计时机制中的作用。来自果蝇和其他系统的越来越多的证据表明，转录后调控机制增加了昼夜节律转录反馈环的动态范围，给它们加上了适时的生化限制，这不仅赋予这些环精确的约24小时的每日周期，还赋予它们整合并快速响应多种环境线索的能力，从而使它们的相位能与当前的外部条件最佳对齐。
