Circadian clock disruption engages the DREAM complex in suppressing cellular health

Circadian clock disruption and lack of sleep impair health of cells and organs, but mechanisms remain elusive. Here, we used multi-omics, molecular and functional assays in three model systems ( C. elegans , human retinal cells and mouse brain) to identify the DREAM complex as a ubiquitous health repressor acting downstream of clock impairment. We show that clock dysfunction aberrantly activates DREAM leading to simultaneous de-regulation of multiple cellular processes. The affected activities including translation, stress responses and OXPHOS are basic and ubiquitous, explaining pan-cellular decline induced by impaired clock and sleep. Accordingly, inhibition of DREAM restores healthy homeostasis and alleviates de-regulation of adaptive mechanisms in clock-impaired nematodes and human cells. This restorative effect occurs amid persisting clock dysfunction, suggesting that DREAM ablation uniquely uncouples circadian clock impairments from their negative effects on health. Our study coins DREAM as a new therapeutic target for preserving organismal fitness under re-current circadian dysfunction.