Dr. Deb Bell-Pedersen | Pedersen Lab

Abstract:
The circadian clock is a fundamental regulator of human health and drug metabolism, coordinating daily rhythms in protein production that affect cellular function and metabolism. Many proteins that cycle robustly are produced from nonrhythmic mRNAs, pointing to translational control as a key mechanism of rhythmic protein levels. Using the model eukaryote Neurospora crassa, we discovered that the clock exerts this regulation through rhythmic control of a conserved translation initiation factor (eIF2α) and by remodeling ribosome composition. Even more unexpectedly, we discovered that the circadian system governs the fidelity of protein synthesis by modulating ribosome makeup and tRNA synthetase activity. Both translational fidelity and circadian amplitude decline with age. We identified compounds that restore clock amplitude in old N. crassa cells, leading to improved translation accuracy and extended lifespan. These findings reveal how the circadian clock programs daily changes in the proteome beyond genomic instructions and highlight a novel link among circadian regulation, proteome integrity and aging.