PER2

Per2, or period circadian regulator 2, is a core component of the mammalian circadian clock. It encodes a transcriptional repressor that participates in the negative feedback loop that generates approximately 24-hour rhythms in gene expression. PER2 protein accumulates in the cytoplasm, then translocates to the nucleus to form complexes with cryptochrome proteins (CRY1/CRY2) and the CLOCK-BMAL1 transcription factor, repressing transcription of their own and other target genes.

Expression of PER2 is driven by CLOCK-BMAL1 and exhibits circadian oscillation. Its stability and subcellular localization are regulated by phosphorylation, predominantly by casein kinase 1 delta and epsilon (CK1δ/ε); phosphorylation marks PER2 for ubiquitination and proteasomal degradation, shaping the period length of the clock.

In the mammalian clock, light input resets the clock by inducing Per gene expression in the suprachiasmatic nucleus (SCN) via signaling pathways including CREB. PER2 participates in integrating environmental timing cues with the internal oscillator.

Beyond timekeeping, PER2 has been implicated in metabolic regulation and tumor suppression in some studies, and PER2 mutations can perturb sleep timing. Notably, mutations in PER2 are associated with familial advanced sleep phase syndrome, a condition characterized by unusually early sleep and wake times, though such associations are relatively rare.

Per2 is conserved across vertebrates and interacts with other clock components as part of an interlocking feedback loop that generates robust circadian rhythms. Dysregulation of PER2 expression or function is observed in various disease states linked to circadian disruption, highlighting its role in coordinating physiology with the 24-hour day.