SCFFbxl3 Controls the
Oscillation of the Circadian Clock by Directing the Degradation of
Cryptochrome Proteins.
L. Busino, F. Bassermann, A. Maiolica, C Lee, S. Godinho, P. Nolan, G.
Draetta and M. Pagano
Science, 316:900-904, 2007.
One component of the circadian clock is the Clock:Bmal1 heterodimeric transcription factor. Among its downstream targets, two genes, Cry1 and Cry2, encode inhibitors of Clock:Bmal1 that establish a negative-feedback loop. Here we report that both Cry1 and Cry2 proteins are ubiquitylated 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 produces no effect in Cry1-/-;Cry2-/- cells, demonstrating that Fbxl3 controls clock oscillations by mediating the degradation of CRY proteins.
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Supplemental Material
Perspective in Science
Perspective in Cell
Michele Pagano at Clocks &
Rhythms Symposium (Cold Spring Harbor) (plug-in required)