FIG. 2.

A simplified and generalized schematic of the mammalian circadian transcriptional-translational feedback loop. [1] RORα/β activates expression of Bmal1, a bHLH transcription factor. [2] BMAL1 protein heterodimerizes with a partner, such as CLOCK, at promoter sites containing E-box consensus motifs (CACGTG) to activate expression of myriad output genes including repressors Period1/2, Cryptochrome1/2, and Rev-Erbα/β, which are subject to a series of post-translational modifications (not shown) that license them for nuclear entry later in the cycle. [3] PER and CRY repress the activity of BMAL1 complexes, inhibiting transcription at their cognate promoter elements and other “clock-controlled genes”. REV-ERBα/β repress expression of Bmal1 and at other loci that are regulated by proximal-promoter elements containing the RORE consensus motif. The repressor protein mRNA and proteins are eventually targeted for proteasomal degradation allowing the cycle to begin afresh. This cycle occurs with a period of ∼24 h. bHLH, basic helix-loop-helix; CLOCK, Circadian Locomotor Output Cycles Kaput; RORE, RAR-related orphan receptor element.