Circadian clocks are modulated by compartmentalized oscillating translation

Area of Science:

• Molecular Biology
• Chronobiology
• Cellular Biology

Background:

• Circadian rhythms are fundamental for terrestrial life, requiring precise diurnal oscillations in biological processes.
• Rhythmic shifts in the cellular translational landscape are crucial for circadian timing, but regulatory mechanisms remain poorly understood.

Purpose of the Study:

• To identify master regulators of rhythmic translation in mammals.
• To elucidate the mechanisms by which these regulators control circadian rhythmicity.

Main Methods:

• Investigated the roles of ATXN2 and ATXN2L in the suprachiasmatic nucleus of mice.
• Utilized depletion and rescue experiments with wild-type and phase-separation-defective ATXN2.
• Analyzed effects on circadian period, translational activation cycles, and gene expression.

Main Results:

• ATXN2 and ATXN2L were identified as cooperating master regulators of rhythmic translation.
• These proteins form spatiotemporal oscillating condensates in the suprachiasmatic nucleus.
• Depletion of ATXN2 or ATXN2L caused opposite alterations in circadian period, while absence of both disrupted rhythmicity.
• Phase-separation-defective ATXN2 failed to rescue the observed cellular defects.

Conclusions:

• Oscillating translation is regulated by the spatiotemporal condensation of ATXN2 and ATXN2L.
• These master regulators are essential for achieving precise circadian rhythms in mammals.
• The findings reveal a novel mechanism for controlling fundamental biological timing.