Immediate nuclear accumulation of BMAL1 to regulate cellular circadian clock synchronization

Area of Science:

• Chronobiology
• Molecular Biology
• Cell Biology

Background:

• Cell-autonomous circadian clocks regulate daily physiological rhythms.
• Environmental cues synchronize these internal clocks.
• The initial signaling events linking cues to clock synchronization are not well understood.

Purpose of the Study:

• To identify common signaling events underlying circadian clock synchronization.
• To investigate the role of BMAL1 and CLOCK protein localization in clock resetting.

Main Methods:

• Investigated BMAL1 and CLOCK localization patterns in NIH-3T3 fibroblasts.
• Utilized various clock-resetting treatments.
• Examined BMAL1-Ser90 phosphorylation by CK2.
• Employed pharmacological CK2 inhibition.
• Performed computational simulations.

Main Results:

• Synchronized nuclear BMAL1 accumulation observed as an immediate synchronization response (ISR).
• CLOCK accumulation also occurred following clock-resetting treatments.
• BMAL1-Ser90 phosphorylation by CK2 was immediately elevated.
• Pharmacological CK2 inhibition partially suppressed Per2 increase and clock reset.
• Computational models supported BMAL1 phosphorylation and nuclear localization in clock resetting.

Conclusions:

• Changes in clock protein localization, specifically BMAL1 nuclear accumulation (BMAL1-ISR), serve as a common synchronizing event.
• BMAL1-ISR acts as an integrative signal linking molecular clock oscillations and environmental cues.
• CK2-mediated BMAL1 phosphorylation is a key component of the circadian clock synchronization mechanism.