This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, J.
Right arrow Articles by Kim, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, J.
Right arrow Articles by Kim, K.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 2008, p. 6056-6065, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00583-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Dual Modification of BMAL1 by SUMO2/3 and Ubiquitin Promotes Circadian Activation of the CLOCK/BMAL1 Complex{triangledown} ,{dagger}

Jiwon Lee, Yool Lee, Min Joo Lee, Eonyoung Park, Sung Hwan Kang, Chin Ha Chung, Kun Ho Lee,* and Kyungjin Kim*

School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea

Received 10 April 2008/ Returned for modification 7 May 2008/ Accepted 11 July 2008

Heterodimers of BMAL1 and CLOCK drive rhythmic expression of clock-controlled genes, thereby generating circadian physiology and behavior. Posttranslational modifications of BMAL1 play a key role in modulating the transcriptional activity of the CLOCK/BMAL1 complex during the circadian cycle. Recently, we demonstrated that circadian activation of the heterodimeric transcription factor is accompanied by ubiquitin-dependent proteolysis of BMAL1. Here we show that modification by SUMO localizes BMAL1 exclusively to the promyelocytic leukemia nuclear body (NB) and simultaneously promotes its transactivation and ubiquitin-dependent degradation. Under physiological conditions, BMAL1 was predominantly conjugated to poly-SUMO2/3 rather than SUMO1, and the level of these conjugates underwent rhythmic variation, peaking at times of maximum E-box-mediated circadian transcription. Interestingly, mutation of the sumoylation site (Lys259) of BMAL1 markedly inhibited both its ubiquitination and its proteasome-mediated proteolysis, and these effects were reversed by covalent attachment of SUMO3 to the C terminus of the mutant BMAL1. Consistent with this, SUSP1, a SUMO protease highly specific for SUMO2/3, abolished ubiquitination, as well as sumoylation of BMAL1, while the ubiquitin protease UBP41 blocked BMAL1 ubiquitination but induced accumulation of polysumoylated BMAL1 and its localization to the NB. Furthermore, inhibition of proteasome with MG132 elicited robust nuclear accumulation of SUMO2/3- and ubiquitin-modified BMAL1 that was restricted to the transcriptionally active stage of the circadian cycle. These results indicate that dual modification of BMAL1 by SUMO2/3 and ubiquitin is essential for circadian activation and degradation of the CLOCK/BMAL1 complex.

* Corresponding author. Mailing address for Kun H. Lee: School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Phone: 82-2-873-6690. Fax: 82-2-872-1993. E-mail: leekho{at}snu.ac.kr. Mailing address for Kyungjin Kim: Neuroendocrine Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea. Phone: 82-2-880-6694. Fax: 82-2-884-6560. E-mail: kyungjin{at}snu.ac.kr

{triangledown} Published ahead of print on 21 July 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, October 2008, p. 6056-6065, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00583-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hung, H.-C., Maurer, C., Zorn, D., Chang, W.-L., Weber, F. (2009). Sequential and Compartment-specific Phosphorylation Controls the Life Cycle of the Circadian CLOCK Protein. J. Biol. Chem. 284: 23734-23742 [Abstract] [Full Text]  
  • Guo, B., Sharrocks, A. D. (2009). Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Signaling Initiates a Dynamic Interplay between Sumoylation and Ubiquitination To Regulate the Activity of the Transcriptional Activator PEA3. Mol. Cell. Biol. 29: 3204-3218 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»