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Science 337 (6094): 599-602

Copyright © 2012 by the American Association for the Advancement of Science

Feedback Regulation of Transcriptional Termination by the Mammalian Circadian Clock PERIOD Complex

Kiran Padmanabhan,1,* Maria S. Robles,1,{dagger} Thomas Westerling,2 Charles J. Weitz1,{ddagger}

Abstract: Eukaryotic circadian clocks are built on transcriptional feedback loops. In mammals, the PERIOD (PER) and CRYPTOCHROME (CRY) proteins accumulate, form a large nuclear complex (PER complex), and repress their own transcription. We found that mouse PER complexes included RNA helicases DDX5 and DHX9, active RNA polymerase II large subunit, Per and Cry pre-mRNAs, and SETX, a helicase that promotes transcriptional termination. During circadian negative feedback, RNA polymerase II accumulated near termination sites on Per and Cry genes but not on control genes. Recruitment of PER complexes to the elongating polymerase at Per and Cry termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. Circadian clock negative feedback thus includes direct control of transcriptional termination.

1 Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
2 Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 USA.

* Present address: Institut Albert Bonniot, Grenoble 38006, France.

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

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


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