Journal
MOLECULAR CELL
Volume 48, Issue 2, Pages 277-287Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2012.08.012
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Funding
- Swiss National Foundation [SNF 31-113565, SNF 31-128656/1]
- NCCR
- European Research Council [ERC-2009-AdG 20090506, ERC-2010- StG-260667]
- State of Geneva
- Louis Jeantet Foundation of Medicine
- Swiss National Foundation (SNF) [31-130714]
- Ecole Polytechnique de Lausanne (EPFL)
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The transcription factors BMAL1 and CLOCK drive the circadian transcription of clock and clock-controlled genes, such as Dbp. To investigate the kinetics of BMAL1 binding to target genes in real time, we generated a cell line harboring tandem arrays of Dbp repeats and monitored the binding of a fluorescent BMAL1 fusion protein to these arrays by time-lapse microscopy. BMAL1 occupancy at the Dbp locus was highly circadian and strictly dependent on CLOCK. Moreover, BMAL1-CLOCK associations with Dbp were extremely unstable and displayed stochastic, proteasome-dependent fluctuations. Proteasome inhibition prolonged the residence time of BMAL1-CLOCK but resulted in an immediate attenuation of Dbp transcription. In cells harboring a single Dbp-luciferase reporter gene copy, this silencing was shown to be caused by a decrease in both the frequencies and sizes of transcriptional bursts. Thus, BMAL1 and CLOCK may act as Kamikaze activators, in that they are rapidly degraded once bound to Dbp chromatin.
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