Fig. 1

The core molecular circadian clock mechanism. Twenty-four-hour cellular rhythms are driven by an autoregulatory feedback loop. During the subjective day, RORα contributes to expression of Bmal1 through its retinoic acid-related orphan receptor response element (RRE). The resulting CLOCK/BMAL1 complex activates transcription of the negative regulators, Per and Cry. By the evening PER and CRY levels accumulate to form a protein complex, which then becomes active as a CLOCK/BMAL1 inhibitor. During the subjective night, REV-ERBα suppresses expression of Bmal1, while the newly formed PER/CRY complex blocks CLOCK/BMAL1 activity, thereby preventing further transcription from the Per and Cry genes. During this time, the phosphorylated PER/CRY complex gradually degrades