CLOSING THE CIRCADIAN LOOP - CLOCK-INDUCED TRANSCRIPTION OF ITS OWN INHIBITORS PER AND TIM

The circadian oscillator generates a rhythmic output with a period of about 24 hours. Despite extensive studies in several model systems, th e 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 period and timeless. dCLO CK functioned as a heterodimer with a Drosophila homolog of BMAL1. The se proteins acted through an E-box sequence in the period promoter. Th e timeless promoter contains an 18-base pair element encompassing an E -box, which was sufficient to confer dCLOCK responsiveness to a report er gene. PERIOD and TIMELESS proteins blocked dCLOCK's ability to tran sactivate their promoters via the E-box. Thus, dCLOCK drives expressio n of period and timeless, which in turn inhibit dCLOCK's activity and close the circadian loop.