Circadian Biology in Humans | Molecular Biology of Circadian Rhythms

Initial information on the generation of circadian rhythms at the molecular level was obtained from multiple studies in Drosophila species, in which expression of the genes Period (Per) and Timeless (Tim) serve to control the circadian clock.  Subsequently, in all species of animals studied, the mechanisms involved in genetic expression and protein production all depend on tightly controlled coordination and expression of specific clock genes.

In mammalian species, the predominant control genes are the Period genes (Per1, Per2, and Per3) and Cryptochrome genes (Cry1 and Cry2).  The protein products of gene expression oscillate over the 24-hour cycle by an intricate negative feedback mechanism in which their promoters are inhibited.  Permanently attached to these promoters is a dimer consisting of two transcriptional activator proteins, CLOCK and B-MAL 1 (brain-muscle aryl hydrocarbon receptor nuclear translocator-like protein 1).

In mammalian circadian rhythms, the 24-hour cycle of clock gene expression proceeds as follows:

1. In the morning, the CLOCK and B-MAL 1 transcriptional activator proteins in the cell nucleus activate the promoters of the Cry and Per genes, and produce mRNA transcripts.
2. These mRNA transcripts are exported into the cytoplasm.
3. As the day progresses, ribosomes bind to these mRNA molecules and translate their genetic code into proteins.
4. Later in the day, PER (1,2, and 3) and CRY (1 and 2) proteins accumulate in the cytoplasm.
5. In the evening, CRY and PER molecules bind to each other by phosphorylation.
6. At night, the CRY/PER complexes enter the nucleus in a coordinated fashion.
7. During the rest of the night, the CRY/PER complexes inhibit the transcriptional activators CLOCK and B-MAL 1, therefore interrupting further formation of Cry and Per mRNA.
8. Cry and Per mRNA and CRY and PER proteins degrade and disappear toward early morning, thereby releasing their inhibition on the transcriptional activators CLOCK and B-MAL 1 and the cycle repeats itself.

The mechanisms that regulate each individual’s circadian period with such precision are complex and, consequently, mutations in the different clock genes can affect the circadian rhythm and period length.