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.

Published Online August 18, 2005
Science DOI: 10.1126/science.1110689

Reports

Submitted on February 4, 2005
Accepted on July 25, 2005

Circadian Clock Control by SUMOylation of BMAL1

Luca Cardone 1, Jun Hirayama 1, Francesca Giordano 1, Teruya Tamaru 2, Jorma J. Palvimo 3, Paolo Sassone-Corsi 1*

1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404 Illkirch, Strasbourg, France.
2 Department of Physiology, Toho University School of Medicine, 5-21-16 Ohmori-nishi Ohta-ku, Tokyo 143-8540, Japan.
3 Biomedicum Helsinki, Institute of Biomedicine, Post Office Box 63, University of Helsinki, 00014 Helsinki, Finland.

* To whom correspondence should be addressed.
Paolo Sassone-Corsi , E-mail: paolosc{at}igbmc.u-strasbg.fr

The molecular machinery that governs circadian rhythmicity is based on clock proteins organized in regulatory feedback loops. Although posttranslational modification of clock proteins is likely to finely control their circadian functions, only limited information is available to date. Here, we show that BMAL1, an essential component of the clock mechanism, is SUMOylated in vivo. A highly conserved lysine residue (Lys259) in the PAS domain linker region constitutes the key SUMO acceptor site. BMAL1 shows a circadian pattern of SUMOylation in mouse liver, an event that tightly parallels its activation. SUMOylation of BMAL1 requires and is induced by CLOCK, the heterodimerization partner of BMAL1. Ectopic expression of a SUMO-deficient BMAL1 with the use of viral vector demonstrates that SUMOylation plays an important role in BMAL1 circadian expression and clock rhythmicity. Our findings reveal a yet unappreciated level of regulation within the core mechanism of the circadian clock.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
How nuclear receptors tell time.
M. Teboul, A. Grechez-Cassiau, F. Guillaumond, and F. Delaunay (2009)
J Appl Physiol 107, 1965-1971
   Abstract »    Full Text »    PDF »
Rev-erb-{alpha}: an integrator of circadian rhythms and metabolism.
H. Duez and B. Staels (2009)
J Appl Physiol 107, 1972-1980
   Abstract »    Full Text »    PDF »
Sequential and Compartment-specific Phosphorylation Controls the Life Cycle of the Circadian CLOCK Protein.
H.-C. Hung, C. Maurer, D. Zorn, W.-L. Chang, and F. Weber (2009)
J. Biol. Chem. 284, 23734-23742
   Abstract »    Full Text »    PDF »
Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications.
N. Nader, G. P. Chrousos, and T. Kino (2009)
FASEB J 23, 1572-1583
   Abstract »    Full Text »    PDF »
Quality Control of a Transcriptional Regulator by SUMO-Targeted Degradation.
Z. Wang and G. Prelich (2009)
Mol. Cell. Biol. 29, 1694-1706
   Abstract »    Full Text »    PDF »
Pax8 protein stability is controlled by sumoylation.
T. de Cristofaro, A. Mascia, A. Pappalardo, B. D'Andrea, L. Nitsch, and M. Zannini (2009)
J. Mol. Endocrinol. 42, 35-46
   Abstract »    Full Text »    PDF »
Dual Modification of BMAL1 by SUMO2/3 and Ubiquitin Promotes Circadian Activation of the CLOCK/BMAL1 Complex.
J. Lee, Y. Lee, M. J. Lee, E. Park, S. H. Kang, C. H. Chung, K. H. Lee, and K. Kim (2008)
Mol. Cell. Biol. 28, 6056-6065
   Abstract »    Full Text »    PDF »
Circadian Organization oftau Mutant Hamsters: Aftereffects and Splitting.
E. L. Bittman, M. K. Costello, and J. McKinley Brewer (2007)
J Biol Rhythms 22, 425-431
   Abstract »    PDF »
The After-Hours Mutant Reveals a Role for Fbxl3 in Determining Mammalian Circadian Period.
S. I. H. Godinho, E. S. Maywood, L. Shaw, V. Tucci, A. R. Barnard, L. Busino, M. Pagano, R. Kendall, M. M. Quwailid, M. R. Romero, et al. (2007)
Science 316, 897-900
   Abstract »    Full Text »    PDF »
Chromatin Remodeling and Circadian Control: Master Regulator CLOCK Is an Enzyme.
B. Grimaldi, Y. Nakahata, S. Sahar, M. Kaluzova, D. Gauthier, K. Pham, N. Patel, J. Hirayama, and P. Sassone-Corsi (2007)
Cold Spring Harb Symp Quant Biol 72, 105-112
   Abstract »    PDF »
Role of Phosphorylation in the Mammalian Circadian Clock.
K. Vanselow and A. Kramer (2007)
Cold Spring Harb Symp Quant Biol 72, 167-176
   Abstract »    PDF »
Molecular components of the mammalian circadian clock.
C. H. Ko and J. S. Takahashi (2006)
Hum. Mol. Genet. 15, R271-R277
   Abstract »    Full Text »    PDF »
BMAL1 Shuttling Controls Transactivation and Degradation of the CLOCK/BMAL1 Heterodimer..
I. Kwon, J. Lee, S. H. Chang, N. C. Jung, B. J. Lee, G. H. Son, K. Kim, and K. H. Lee (2006)
Mol. Cell. Biol. 26, 7318-7330
   Abstract »    Full Text »    PDF »
The BMAL1 C terminus regulates the circadian transcription feedback loop.
Y. B. Kiyohara, S. Tagao, F. Tamanini, A. Morita, Y. Sugisawa, M. Yasuda, I. Yamanaka, H. R. Ueda, G. T. J. van der Horst, T. Kondo, et al. (2006)
PNAS 103, 10074-10079
   Abstract »    Full Text »    PDF »
MafG Sumoylation Is Required for Active Transcriptional Repression.
H. Motohashi, F. Katsuoka, C. Miyoshi, Y. Uchimura, H. Saitoh, C. Francastel, J. D. Engel, and M. Yamamoto (2006)
Mol. Cell. Biol. 26, 4652-4663
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)