SCF Fbxl3 Controls the Oscillation of the Circadian Clock by Directing the Degradation of Cryptochrome Proteins

Abstract

One component of the circadian clock in mammals is the Clock-Bmal1 heterodimeric transcription factor. Among its downstream targets, two genes, Cry1 and Cry2 , encode inhibitors of the Clock-Bmal1 complex that establish a negative-feedback loop. We found that both Cry1 and Cry2 proteins are ubiquitinated and degraded via the SCF Fbxl3 ubiquitin ligase complex. This regulation by SCF Fbxl3 is a prerequisite for the efficient and timely reactivation of Clock-Bmal1 and the consequent expression of Per1 and Per2 , two regulators of the circadian clock that display tumor suppressor activity. Silencing of Fbxl3 produced no effect in Cry1 –/– ; Cry2 –/– cells, which shows that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins.