ArticleMolecular and cellular biology2008
Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex.
Article in Molecular and cellular biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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Who cites it
92 citing papers in PubMed, 159 citations in OpenAlex.
- Environmental cues signal through circadian control of sarcomeric gene expression during cardiomyocyte hypertrophy.Epigenetics · 2026Article
- BMAL1 in cardiovascular diseases: Molecular mechanisms, circadian regulation and translational perspectives (Review).Molecular medicine reports · 2026Review
- Post-Translational Modifications in Animal Circadian Clocks.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Disordered but rhythmic-the role of intrinsic protein disorder in eukaryotic circadian timing.FEBS letters · 2026Review
- Glucocorticoid Receptor and SUMO Fluctuations in Response to Pulsatile Glucocorticoids In Vitro and in Male Rat Brains.Endocrinology · 2025Article
- O-GlcNAcylation of nuclear proteins in the mouse liver exhibit daily oscillations that are influenced by meal timing.PLoS biology · 2025Article
- Mealtime alters daily rhythm in nuclear O-GlcNAc proteome to regulate hepatic gene expression.bioRxiv : the preprint server for biology · 2025Article
- Rhythms in Remodeling: Posttranslational Regulation of Bone by the Circadian Clock.Biomedicines · 2025Review
- Circadian rhythms in stem cells and their therapeutic potential.Stem cell research & therapy · 2025Review
- Circadian patterns of growth factor receptor-dependent signaling and implications for carcinogenesis.Cell communication and signaling : CCS · 2024Review
- On the Prevalence and Roles of Proteins Undergoing Liquid-Liquid Phase Separation in the Biogenesis of PML-Bodies.Biomolecules · 2023Article
- Review
- Beyond metabolic waste: lysine lactylation and its potential roles in cancer progression and cell fate determination.Cellular oncology (Dordrecht, Netherlands) · 2023Review
- Article
- Potential Role of the Circadian Clock in the Regulation of Cancer Stem Cells and Cancer Therapy.International journal of molecular sciences · 2022Review
- The molecular clockwork of mammalian cells.Seminars in cell & developmental biology · 2022Review
- Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks.Biology · 2021Review
- Circadian Rhythms, Disease and Chronotherapy.Journal of biological rhythms · 2021Review
- REGγ regulates circadian clock by modulating BMAL1 protein stability.Cell death discovery · 2021Article
- Translating around the clock: Multi-level regulation of post-transcriptional processes by the circadian clock.Cellular signalling · 2021Review
32 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 (Lys(259)) 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.
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