Sleep and circadian regulation of DNA repair and retrotransposons in neuronal genome stability and neurodegenerative disease mechanisms.

Sleep and wake are fundamental brain states that coordinate diverse physiological processes required for long-term health and survival. Recent research in molecular neuroscience and chronobiology has begun to clarify how sleep-wake cycles and circadian timing intersect with genomic maintenance mechanisms in the nervous system. In this Review, we summarize current evidence that sleep and circadian rhythms temporally regulate neuronal genome stability, with a particular focus on how they modulate neuronal retrotransposon activity. We discuss circadian clock-dependent regulation of DNA repair pathways, the contribution of sleep to chromosomal integrity and chromosome dynamics, and emerging data on temporally-dependent retrotransposon activity across the sleep-wake cycle. Taken together, the studies we review suggest that sleep may provide a permissive state during which neurons engage genome-protective processes, including up-regulation of DNA repair factors, changes in chromatin organization, and silencing of retrotransposon activity. We further propose that these mechanisms may be relevant to neurodegenerative disorders, although much of the current evidence linking sleep and circadian disruption to retrotransposon dysregulation, genomic instability, and cognitive decline remains preclinical or correlative in humans.