Circadian control by the reduction/oxidation pathway: Catalase represses light-dependent clock gene expression in the zebrafish

Abstract

Light is the key entraining stimulus for the circadian clock, but several features of the signaling pathways that convert the photic signal to clock entrainment remain to be deciphered. Here, we show that light induces the production of hydrogen peroxide (H2O2) that acts as the second messenger coupling photoreception to the zebrafish circadian clock. Treatment of light-responsive Z3 cells with H2O2 triggers the induction of zCry1a and zPer2 genes and the subsequent circadian oscillation of zPer1. Remarkably, the induction kinetics and oscillation profile in response to H2O2 are identical to those initiated by light. Catalase (Cat), an antioxidant enzyme degrading H2O2, shows an oscillating pattern of expression and activity, antiphasic to zCry1a and zPer2. Interestingly, overexpression of zCAT results in a reduced light-dependent zCry1a and zPer2 gene induction. In contrast, inhibition of zCAT function enhances light-mediated inducibility of these clock genes. These findings implicate the enzymatic function of zCAT enzyme in the negative regulation of light-dependent clock gene transcriptional activation. Our findings provide an attractive link between the regulation of the cellular reduction/oxidation (redox) state and the photic signaling pathways implicated in circadian control.light signaling ͉ hydrogen peroxide ͉ transcription ͉ circadian rhythms

A Common Origin: Signaling Similarities in the Regulation of the Circadian Clock and DNA Damage Responses

“…57,63,64) Indeed, there is evidence that light-induced zCRY1a is a transcriptional repressor essential for the light-dependent entrainment of the circadian clock. 63) The light-dependent transcription of zCry1a is controlled through the production and removal of cellular reactive oxygen species (ROS).…”

“…65,67) In zebrafish cells, this light-induced redox change stimulates intracellular MAPK signaling that transduces photic signals to zCry1a transactivation. 57) Importantly, light also increases intracellular catalase activity by stimulating catalase transcription, an event that occurs after the maximum expression of the zCry1a gene has been reached. 57) This increased catalase activity diminishes light-induced cellular ROS levels, resulting in decreased zCry1a transcription and creating a negative feedback loop.…”

“…87) In the diatom Phaeodactylum tricornutum, PtCPF1 (Phaeodactylum tricornutum cryptochrome/photolyase family 1) is a novel cryptochrome/photolyase family member that not only repairs UV-induced DNA damage but also acts as a transcriptional repressor of the circadian clock. 88) In addition, the critical role of redox signaling in the light-dependent entrainment of the circadian clock 57,68) strongly implicates cellular responses to the toxic effects of sunlight as the evolutionary origin of circadian rhythms.…”

“…81) This mechanism is consistent with the observation that the growth of cultured zebrafish cells is suppressed by light. 60) Because solar light increases intracellular ROS levels that can exert oxidative stress, 57,65) light-induced zWee1 expression may act as a cellular stress response, suppressing cell growth under conditions where DNA damage is likely (Fig. 4).…”

“…6,50) There are three major MAPKs: c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK). 72) Light-induced ROS production in zebrafish cells leads to downstream activation of MAPK cascades, which then contribute to the regulation of zCry1a transcription 52,57) (Fig. 2).…”