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.


Logo for

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}

Variants in glucose- and circadian rhythm-related genes affect the response of energy expenditure to weight-loss diets: the POUNDS LOST Trial.
K. Mirzaei, M. Xu, Q. Qi, L. de Jonge, G. A. Bray, F. Sacks, and L. Qi (2014)
Am J Clin Nutr 99, 392-399
   Abstract »    Full Text »    PDF »
The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis.
M. Liu, A. Roth, M. Yu, R. Morris, F. Bersani, M. N. Rivera, J. Lu, T. Shioda, S. Vasudevan, S. Ramaswamy, et al. (2013)
Genes & Dev. 27, 2543-2548
   Abstract »    Full Text »    PDF »
A positive feedback loop links circadian clock factor CLOCK-BMAL1 to the basic transcriptional machinery.
L. Lande-Diner, C. Boyault, J. Y. Kim, and C. J. Weitz (2013)
PNAS 110, 16021-16026
   Abstract »    Full Text »    PDF »
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 305, R735-R747
   Abstract »    Full Text »    PDF »
Mechanism of the circadian clock in physiology.
J. Richards and M. L. Gumz (2013)
Am J Physiol Regulatory Integrative Comp Physiol 304, R1053-R1064
   Abstract »    Full Text »    PDF »
Distinguishing Core and Holoenzyme Mechanisms of Transcription Termination by RNA Polymerase III.
A. G. Arimbasseri and R. J. Maraia (2013)
Mol. Cell. Biol. 33, 1571-1581
   Abstract »    Full Text »    PDF »
Transcriptional Architecture and Chromatin Landscape of the Core Circadian Clock in Mammals.
N. Koike, S.-H. Yoo, H.-C. Huang, V. Kumar, C. Lee, T.-K. Kim, and J. S. Takahashi (2012)
Science 338, 349-354
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882