Evolution Shapes the Gene Expression Response to Oxidative Stress.

Reactive oxygen species (ROS) play a key role in cell physiology and function. ROS represents a potential source of damage for many macromolecules including DNA. It is thought that daily changes in oxidative stress levels were an important early factor driving evolution of the circadian clock which enables organisms to predict changes in ROS levels before they actually occur and thereby optimally coordinate survival strategies. It is clear that ROS, at relatively low levels, can serve as an important signaling molecule and also serves as a key regulator of gene expression. Therefore, the mechanisms that have evolved to survive or harness these effects of ROS are ancient evolutionary adaptations that are tightly interconnected with most aspects of cellular physiology. Our understanding of these mechanisms has been mainly based on studies using a relatively small group of genetic models. However, we know comparatively little about how these mechanisms are conserved or have adapted during evolution under different environmental conditions. In this review, we describe recent work that has revealed significant species-specific differences in the gene expression response to ROS by exploring diverse organisms. This evidence supports the notion that during evolution, rather than being highly conserved, there is inherent plasticity in the molecular mechanisms responding to oxidative stress.

Evolution shapes the responsiveness of the D-box enhancer element to light and reactive oxygen species in vertebrates.

The circadian clock is a highly conserved cell-autonomous mechanism that directs daily rhythms in most aspects of biology. Daily entrainment by environmental signals, notably light, is essential for its function. However, our understanding of the mechanisms and the evolution of photic entrainment remains incomplete. Fish represent attractive models for exploring how light regulates the circadian clock due to the direct light sensitivity of their peripheral clocks. Central to this property is the light induced expression of clock genes that is mediated by D-box enhancer elements. Here, using zebrafish cells, we reveal that the light responsive D-box enhancer serves as a nuclear target for reactive oxygen species (ROS). We demonstrate that exposure to short wavelengths of visible light triggers increases in ROS levels via NADPH oxidase activity. Elevated ROS activates the JNK and p38 MAP kinases and in turn, induces clock gene expression via the D-box. In blind cavefish and mammals, where peripheral clocks are no longer entrained by direct illumination, ROS levels are still increased upon light exposure. However, in these species ROS no longer induces D-box driven clock gene transcription. Thus, during evolution, alterations in ROS-responsive signal transduction pathways underlie fundamental changes in peripheral clock photoentrainment.

The tumor-associated YB-1 protein: new player in the circadian control of cell proliferation.

Correct spatial and temporal control of cell proliferation is of fundamental importance for tissue homeostasis. Its deregulation has been associated with several pathological conditions. In common with almost every aspect of plant and animal biology, cell proliferation is dominated by day-night rhythms generated by the circadian clock. However, our understanding of the crosstalk between the core clock and cell cycle control mechanisms remains incomplete. In this study, using zebrafish as a vertebrate model system, we show that the nuclear localization of the Y-box binding protein 1 (YB-1), a regulator of cyclin expression and a hallmark of certain cancers, is robustly regulated by the circadian clock. We implicate clock-controlled changes in YB-1 SUMOylation as one of the mechanisms regulating its periodic nuclear entry at the beginning of the light phase. Furthermore, we demonstrate that YB-1 nuclear protein is able to downregulate cyclin A2 mRNA expression in zebrafish via its direct interaction with the cyclin A2 promoter. Thus, by acting as a direct target of cyclic posttranslational regulatory mechanisms, YB-1 serves as one bridge between the circadian clock and its cell cycle control.