Circadian Regulation of a Drosophila Homolog of the Mammalian Clock Gene: PER and TIM Function as Positive Regulators

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Abstract
The Clock gene plays an essential role in the manifestation of circadian rhythms (≅24 h) in mice and is a member of the basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) superfamily of transcription factors. Here we report the characterization of a novelDrosophila bHLH-PAS protein that is highly homologous to mammalian CLOCK. (Similar findings were recently described by Allada et al. Cell 93:791–804, 1998, and Darlington et al., Science 280:1599–1603, 1998.) Transcripts from this putative Clockortholog (designated dClock) undergo daily rhythms in abundance that are antiphase to the cycling observed for the RNA products from the Drosophila melanogaster circadian clock genes period (per) and timeless(tim). Furthermore, dClock RNA cycling is abolished and the levels are at trough values in the absence of either PER or TIM, suggesting that these two proteins can function as transcriptional activators, a possibility which is in stark contrast to their previously characterized role in transcriptional autoinhibition. Finally, the temporal regulation of dClock expression is quickly perturbed by shifts in light-dark cycles, indicating that this molecular rhythm is closely connected to the photic entrainment pathway. The isolation of a Drosophila homolog ofClock together with the recent discovery of mammalian homologs of per indicate that there is high structural conservation in the integral components underlying circadian oscillators in Drosophila and mammals. Nevertheless, because mammalian Clock mRNA is constitutively expressed, our findings are a further example of striking differences in the regulation of putative circadian clock orthologs in different species.