Immediate nuclear accumulation of BMAL1 to regulate cellular circadian clock synchronization.

Cell-autonomous circadian clocks coordinate daily physiological timing, allowing them to synchronize with the environment. However, the initial signaling events shared by diverse synchronizing cues remain elusive. Here, we show that changes in the clock protein localization serve as a common synchronizing event by investigating the relationship between BMAL1 and CLOCK localization patterns and clock synchronization in NIH-3T3 fibroblasts. We demonstrate synchronized nuclear BMAL1 accumulation as an immediate synchronization response (ISR), as well as CLOCK accumulation following various clock-resetting treatments. BMAL1-Ser90 phosphorylation by CK2, which is reported to promote nuclear BMAL1 accumulation, is also immediately elevated. Importantly, pharmacological CK2 inhibition partially suppresses the acute Per2 increase and clock reset. Furthermore, computational simulation supports that an increase in the BMAL1 phosphorylation levels and its subsequent nuclear localization could reset the clock. In summary, our findings suggest that BMAL1-ISR is a key event that acts as an integrative switching signal to link molecular clock oscillation and diverse synchronization cues.