Dynamic condensates enhance the robustness of biological oscillation

Protein/RNA condensates participate in many cellular processes, but their functional roles often remain unclear. We recently found that condensates of the RNA-binding protein ATXN2 oscillate with the circadian cycle, recruit translation machinery and circadian mRNAs such as Per2, and promote translation. Using mathematical modeling, we show that dynamic condensate assembly enhances the robustness and phase coherence of oscillations in a transcription-translation feedback loop (TTFL). This effect cannot be reproduced by simply increasing repressive-protein translation through static condensates. Condensates that oscillate with the core TTFL at an appropriate phase shift can increase protein translation without depleting the corresponding mRNA. Two circuit designs can generate this timing: TTFL-regulated condensate transcription or a hybrid architecture in which an intrinsically oscillatory condensate loop is coupled to the core loop. Knockdown of Per2, Bmal1, and Clock showed residual 24-h ATXN2 condensate oscillations, supporting the hybrid model. A record of this paper's transparent peer review process is included in the supplemental information.