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Sumoylation controls CLOCK-BMAL1-mediated clock resetting via CBP recruitment in nuclear transcriptional foci

Sumoylation controls CLOCK-BMAL1-mediated clock resetting via CBP recruitment in nuclear transcriptional foci
Lee, Y[Lee, Yool]Chun, SK[Chun, Sung Kook]Kim, K[Kim, Kyungjin]
DGIST Authors
Chun, SK[Chun, Sung Kook]Kim, K[Kim, Kyungjin]
Issued Date
Article Type
Amino Acid SubstitutionAnimalAnimal CellAnimalsARNTL Protein, HumanARNTL Transcription FactorsBiFC-Based FRETBMAL1Bone Sialoprotein (35-62), HumanCBPCell NucleusCell Nucleus Inclusion BodyCercopithecus AethiopsChlorocebus AethiopsCircadian ClockCircadian ClocksCircadian RhythmClock Protein, HumanClock ProteinsClock ResettingComplex FormationControlled StudyCOS 1 Cell LineCOS CellsCyclic AMP Responsive Element Binding Protein Binding ProteinCysteine EndopeptidasesCysteine ProteinaseFluorescence Resonance Energy TransferGene ExpressionGeneticsHumanHumansMammaliaMetabolismMolecular DynamicsMutationNon-HumanNuclear BodyPeptide FragmentPeptide FragmentsPER1 ProteinPhysiologyPriority JournalProtein Protein InteractionProtein SUSP1ProteinaseSENP6 Protein, HumanSialoglycoproteinSialoglycoproteinsSUMO3 ProteinSUMO3 Protein, HumanSumoylationSUSP1Transcription Factor ARNTLTranscription Factor ClockTranscription TerminationUbiquitinUbiquitinsUnclassified Drug
CLOCK-BMAL1 is a key transcription factor complex of the molecular clock system that generates circadian gene expression and physiology in mammals. Here, we demonstrate that sumoylation of BMAL1 mediates the rapid activation of CLOCK-BMAL1 by CREB-binding protein (CBP) in nuclear foci and also the resetting of the circadian clock. Under physiological conditions, a bimolecular fluorescence complementation-based fluorescence resonance energy transfer (BiFC-FRET) assay revealed that CLOCK-BMAL1 rapidly dimerized and formed a ternary complex with CBP in discrete nuclear foci in response to serum stimuli. We found that the formation of this ternary complex requires sumoylation of BMAL1 by SUMO3. These processes were abolished by both the ectopic expression of the SUMP2/3-specific protease, SUSP1, and mutation of the major sumoylation site (Lys259) of BMAL1. Moreover, molecular inhibition of BMAL1 sumoylation abrogated acute Per1 transcription and severely dampened the circadian gene oscillation triggered by clock synchronization stimuli. Taken together, these findings suggest that sumoylation plays a critical role in the spatiotemporal co-activation of CLOCK-BMAL1 by CBP for immediate-early Per induction and the resetting of the circadian clock. © 2015.
Elsevier B.V.
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Department of Brain Sciences Brain and BioClock Laboratory 1. Journal Articles


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