CLOCK (yellow) and BMAL1 (purple) proteins (positive limb) heterodimerize and drive the expression of Per, Cry and Rev-erbα genes in the nucleus. PER (red) and CRY (light green) proteins interact in the nucleus to inhibit CLOCK/BMAL1 action by a yet unknown mechanism and thereby down-regulate their own expression and that of Rev-erbα (dark green). When REV-ERBα protein is absent, Bmal1 is derepressed and hence transcribed to produce new CLOCK/BMAL1 transcription factors that reinitiate a new circadian cycle. Clock proteins are posttranslationally modified; casein kinase I (CKI), for example, phosphorylates PER2. Hyperphosphorylation of PER2 promotes its degradation.