Common pathways in circadian and cell cycle clocks: Light-dependent activation of Fos/AP-1 in zebrafish controls CRY-1a and WEE-1

Abstract

The cell cycle and the circadian clock are endogenous pacemakers, which coexist in most eukaryotic cells and share a number of conceptual features. In the zebrafish, light directly regulates the timing of both clocks, although the signaling and transcriptional pathways that convey photic information to essential nuclear regulators have yet to be deciphered. We have previously established the Z3 cell line, which recapitulates the features of zebrafish circadian clock and represents an ideal system to study lightdependent signaling and gene regulation. We conducted a search for light-responsive transcription factors and found that AP-1 DNA binding is highly induced. Light induces the expression of zWee1, a cell cycle gene essential for G2͞M transition, and zCry1a, a clock gene of the feedback regulatory loop. We have found consensus AP-1 sites in the regulatory regions of both zWee1 and zCry1a genes, and we show that light inducibility of both genes is abrogated by inhibition of AP-1 function. Light also elicits chromatin remodeling by stimulating hyperacetylation at Lys-14 of histone H3 at both zWee1 and zCry1a promoters, as assessed by chromatin immunoprecipitation assays by using anti-Fos antibody. These findings provide strong evidence that circadian and cell cycle clocks share unique light-responsive pathways in zebrafish.

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

“…Indeed, light-stimulated AP-1 activity contributes to zCry1a transactivation involved in light entrainment of the circadian clock. 60) Taken together, these findings provide strong evidence that the cell cycle and circadian clock are regulated by a common signaling pathway controlled by AP-1 transcription factor. Sunlight has two major toxic effects: generation of ROS that mediate photo-oxidative stress and induction of UV-mediated DNA damage.…”

“…52,58,59) The dissection of the light signaling pathways used for circadian entrainment in zebrafish peripheral cells has revealed common mediators also shared by pathways used to regulate the cell cycle and DDR. 52,60) …”

“…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).…”

“…83) In zebrafish, light can induce AP-1 activation, which then triggers zWee1 transcription. 60) Components of AP-1 that are acutely light-inducible include c-fos, fos-B and jun-B. 84,85) In mammals, light-dependent activation of AP-1 in the SCN has been implicated in light-induced phase-shifting of the circadian clock.…”

“…58) At the molecular level, light induces the expression of zebrafish Wee1 (zWee1), a cell cycle gene. 60) The Wee1 kinase controls the timing of the G 2 -M transition by directly phosphorylating and thus inhibiting Cdc2/cyclin B, leading to suppression of mitotic cell division. 81) This mechanism is consistent with the observation that the growth of cultured zebrafish cells is suppressed by light.…”