Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
A Molecular Mechanism for Circadian Clock Negative Feedback
Hao A. Duong,*
Maria S. Robles,*,
Charles J. Weitz
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.
Present address: Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany.
Opposing actions of Per1 and Cry2 in the regulation of Per1 target gene expression in the liver and kidney.
J. Richards, S. All, G. Skopis, K.-Y. Cheng, B. Compton, N. Srialluri, L. Stow, L. A. Jeffers, and M. L. Gumz (2013)
Am J Physiol Regulatory Integrative Comp Physiol
|Abstract »|Full Text »|PDF »
Methylation of Histone H3 on Lysine 4 by the Lysine Methyltransferase SET1 Protein Is Needed for Normal Clock Gene Expression.