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Science 308 (5722): 693-696

Copyright © 2005 by the American Association for the Advancement of Science

PERIOD1-Associated Proteins Modulate the Negative Limb of the Mammalian Circadian Oscillator

Steven A. Brown,1* Juergen Ripperger,1 Sebastian Kadener,2 Fabienne Fleury-Olela,1 Francis Vilbois,3 Michael Rosbash,2 Ueli Schibler1*

Abstract: The clock proteins PERIOD1 (PER1) and PERIOD2 (PER2) play essential roles in a negative transcriptional feedback loop that generates circadian rhythms in mammalian cells. We identified two PER1-associated factors, NONO and WDR5, that modulate PER activity. The reduction of NONO expression by RNA interference (RNAi) attenuated circadian rhythms in mammalian cells, and fruit flies carrying a hypomorphic allele were nearly arrhythmic. WDR5, a subunit of histone methyltransferase complexes, augmented PER-mediated transcriptional repression, and its reduction by RNAi diminished circadian histone methylations at the promoter of a clock gene.

1 Department of Molecular Biology and National Centres of Competence in Research (NCCR) Frontiers in Genetics, Sciences III, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva-4, Switzerland.
2 Department of Biology, Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454, USA.
3 Serono Pharmaceutical Research Institute, 14 Chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.

* To whom correspondence should be addressed. E-mail: steven.brown{at}molbio.unige.ch (S.A.B.); Ueli. schibler{at}molbio.unige.ch (U.S.)


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