Biochemical mechanism of the mammalian circadian clock

Circadian rhythms, regulated by core clock proteins, coordinate physiological functions with daily environmental fluctuations across organisms, from bacteria to humans. The circadian clock interacts with various biological processes, and its disruption is associated with numerous human diseases, including sleep disorders, metabolic syndrome, and potentially cancer. In mammals, the circadian clock is driven by cell-autonomous transcription-translation feedback loops (TTFLs), in which CLOCK and BMAL1 act as transcriptional activators, while PER and CRY serve as transcriptional repressors. During the early repression phase, the CRY-PER-CK1 complex binds to CLOCK-BMAL1, displacing it from target promoters. In the late repression phase, in the absence of PER, CRY1 alone inhibits CLOCK-BMAL1 activity by blocking the recruitment of transcriptional coactivators. Biochemical and structural studies have highlighted the essential roles of protein-protein interactions, protein-DNA interactions, and posttranslational modifications in regulating the molecular clock. In this Review, we summarize the molecular mechanisms that govern the circadian clock and focus on the coordination of protein-protein interactions and posttranslational modifications, underscoring the importance of the circadian clock in disease progression and treatment strategies.