The 24-hour cycle of clock gene expression. (a) In the morning, the promoters of the Cry and Per genes are activated by the CLOCK and BMAL1 proteins, producing mRNA transcripts that are exported into the cytoplasm. (b) During the day, ribosomes bind to these mRNA molecules and translate their genetic code into proteins. (c) In the latter part of the day, PER (1, 2 and 3) and CRY (1 and 2) proteins accumulate in the cytoplasm, where CK I (δ and ε) are present constitutively. (d) In the evening, CRY, PER, and CK I molecules bind to each other in different combinations. PER is phosphorylated by CK I, and the complexes enter the nucleus in a coordinated fashion at night. (e) During the rest of the night, the activation of the Cry and Per promoters by CLOCK:BMAL1 is inhibited by the CRY:PER:CK I complex. As a result, production of Cry and Per mRNA is interrupted, which in turn interrupts production of CRY and PER proteins. (f) As both the mRNA and the proteins are short-lived, they will gradually disappear towards the morning. The cycle is complete, and the production of Cry and Per mRNA starts again