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Science 332 (6036): 1436-1439

Copyright © 2011 by the American Association for the Advancement of Science

A Molecular Mechanism for Circadian Clock Negative Feedback

Hao A. Duong,* Maria S. Robles,*,{dagger} Darko Knutti,{ddagger} Charles J. Weitz§

Abstract: Circadian rhythms in mammals are generated by a feedback loop in which the three PERIOD (PER) proteins, acting in a large complex, inhibit the transcriptional activity of the CLOCK-BMAL1 dimer, which represses their own expression. Although fundamental, the mechanism of negative feedback in the mammalian clock, or any eukaryotic clock, is unknown. We analyzed protein constituents of PER complexes purified from mouse tissues and identified PSF (polypyrimidine tract–binding protein–associated splicing factor). Our analysis indicates that PSF within the PER complex recruits SIN3A, a scaffold for assembly of transcriptional inhibitory complexes and that the PER complex thereby rhythmically delivers histone deacetylases to the Per1 promoter, which repress Per1 transcription. These findings provide a function for the PER complex and a molecular mechanism for circadian clock negative feedback.

Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.

* These authors contributed equally to this work.

{dagger} Present address: Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany.

{ddagger} Present address: DSM Nutritional Products, CH-4002 Basel, Switzerland.

§ To whom correspondence should be addressed. E-mail: cweitz{at}hms.harvard.edu

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