SCFFbxl3 Controls the Oscillation of the Circadian Clock by Directing the Degradation of Cryptochrome Proteins

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Science  11 May 2007:
Vol. 316, Issue 5826, pp. 900-904
DOI: 10.1126/science.1141194

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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 SCFFbxl3 ubiquitin ligase complex. This regulation by SCFFbxl3 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.

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