Phosphorylation of CLOCK and BMAL1-a key regulatory mechanism in the mammalian circadian clockwork

In the mammalian circadian clockwork, transcriptional-translational feedback loops are mediated by the core clock proteins, CLOCK and BMAL1. Although the transcriptional activation function of the CLOCK-BMAL1 complex has been well-characterized, the mechanisms underpinning its inactivation, particularly during the repression phase, which is mediated by PER and CRY proteins, remain incompletely understood. Recent studies have shed light on the critical role of phosphorylation within the DNA-binding domains of CLOCK and BMAL1 in modulating their DNA-binding activity and enabling PER-dependent repression. In this review, we summarize landmark studies that collectively delineate a phosphorylation-mediated "displacement" model for CLOCK-BMAL1 inactivation, explore its impact on circadian period regulation, and propose a molecular mechanism that links structural modulation with transcriptional timing.