SCFFbxl3 Controls the Oscillation of the Circadian Clock by Directing the Degradation of Cryptochrome Proteins
Luca Busino,1
Florian Bassermann,1
Alessio Maiolica,2
Choogon Lee,3
Patrick M. Nolan,4
Sofia I. H. Godinho,4
Giulio F. Draetta,5
Michele Pagano1*
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.
1 Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.
2 European Institute of Oncology, 435 Via Ripamonti, 20141 Milan, Italy.
3 Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306, USA.
4 MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, UK.
5 Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
* To whom correspondence should be addressed. E-mail: michele.pagano{at}med.nyu.edu
