Closing the Circadian Loop: CLOCK-Induced Transcription of Its Own Inhibitors per and tim

Science  05 Jun 1998:
Vol. 280, Issue 5369, pp. 1599-1603
DOI: 10.1126/science.280.5369.1599

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The circadian oscillator generates a rhythmic output with a period of about 24 hours. Despite extensive studies in several model systems, the biochemical mode of action has not yet been demonstrated for any of its components. Here, the Drosophila CLOCK protein was shown to induce transcription of the circadian rhythm genes periodand timeless. dCLOCK functioned as a heterodimer with aDrosophila homolog of BMAL1. These proteins acted through an E-box sequence in the period promoter. Thetimeless promoter contains an 18–base pair element encompassing an E-box, which was sufficient to confer dCLOCK responsiveness to a reporter gene. PERIOD and TIMELESS proteins blocked dCLOCK's ability to transactivate their promoters via the E-box. Thus, dCLOCK drives expression of period and timeless,which in turn inhibit dCLOCK's activity and close the circadian loop.

  • * Co–first authors.

  • To whom correspondence should be addressed. E-mail: stevek{at}

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