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Most, if not all organisms exhibit robust rhythmicity of their biological functions, allowing a perpetual adaptation to external clues within the daily 24 hours-cycle. Studies on circadian rhythm regulation primarily focused on transcriptional level, considering mRNA levels to represent the primary determinant of oscillations of intracellular protein levels. However, a plethora of emerging evidence suggests that post-transcriptional regulation, particularly rhythmic mRNA translation, is not solely reliant on the oscillation of transcription. Instead, the circadian regulation of mRNA translation plays a critical role as well. A comprehensive understanding of these mechanisms underlying rhythmic translation and its regulation should bridge the gap in rhythm regulation beyond RNA fluctuations in research, and greatly enhance our comprehension of rhythm generation and maintenance. In this review, we summarize the major mechanisms of circadian regulation of translation, including regulation of translation initiation, elongation, and the alteration in rhythmic translation to external stresses, such as endoplasmic reticulum (ER) stress and ageing. We also illuminate the complex interplay between phase separation and mRNA translation. Together, we have summarized various facets of mRNA translation in circadian regulation, to set on forthcoming studies into the intricate regulatory mechanisms underpinning circadian rhythms and their implications for associated disorders.

Terrestrial organisms developed circadian rhythms for adaptation to Earth's quasi-24-h rotation. Achieving precise rhythms requires diurnal oscillation of fundamental biological processes, such as rhythmic shifts in the cellular translational landscape; however, regulatory mechanisms underlying rhythmic translation remain elusive. Here, we identified mammalian ATXN2 and ATXN2L as cooperating master regulators of rhythmic translation, through oscillating phase separation in the suprachiasmatic nucleus along circadian cycles. The spatiotemporal oscillating condensates facilitate sequential initiation of multiple cycling processes, from mRNA processing to protein translation, for selective genes including core clock genes. Depleting ATXN2 or 2L induces opposite alterations to the circadian period, whereas the absence of both disrupts translational activation cycles and weakens circadian rhythmicity in mice. Such cellular defect can be rescued by wild type, but not phase-separation-defective ATXN2. Together, we revealed that oscillating translation is regulated by spatiotemporal condensation of two master regulators to achieve precise circadian rhythm in mammals. [Display omitted] • ATXN2 and ATXN2L together modulate the mammalian circadian clock • ATXN2/2L phase-separated condensates oscillate and regulate rhythmic translation • ATXN2 condensates recruit ribosomes and selective mRNAs for translational activation • PER2 mRNAs are co-localized and translated within ATXN2 condensates in the SCN ATXN2 and ATXN2L condensates recruit ribosomes and selective mRNAs to regulate translation of key circadian clock genes. [ABSTRACT FROM AUTHOR]