Circadian clock disruption engages the DREAM complex in suppressing cellular health.
Circadian clock disruption and lack of sleep impair organismal health, but remedies remain elusive. Here, we used multi-omics, molecular and functional assays in C. elegans, human retinal cells and mouse brain to identify the DREAM complex as a conserved mediator of sleep and clock benefits at the cellular level. We show that DREAM abundance is under circadian control with high levels seen during wakefulness. DREAM elevation confers increased chromatin compaction and shields DNA from damage while altering fundamental cellular processes such as translation, stress responses and OXPHOS. Conversely, DREAM levels are lowered during sleep enabling cellular maintenance and repair. When sleep or clock are altered, DREAM levels remain high, and repair activities remain suppressed triggering cellular and organismal deterioration that can be reversed by genetic and pharmacological inhibition of DREAM in vivo and in vitro. We thus reveal the potential of DREAM inhibitors to replicate the benefits of sleep in sleep-deprived and clock-impaired organisms.