The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function
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↵1 These authors contributed equally to this work.
Abstract
The human CDK8 subcomplex (CDK8, cyclin C, Med12, and Med13) negatively regulates transcription in ways not completely defined; past studies suggested CDK8 kinase activity was required for its repressive function. Using a reconstituted transcription system together with recombinant or endogenous CDK8 subcomplexes, we demonstrate that, in fact, Med12 and Med13 are critical for subcomplex-dependent repression, whereas CDK8 kinase activity is not. A hallmark of activated transcription is efficient reinitiation from promoter-bound scaffold complexes that recruit a series of pol II enzymes to the gene. Notably, the CDK8 submodule strongly represses even reinitiation events, suggesting a means to fine tune transcript levels. Structural and biochemical studies confirm the CDK8 submodule binds the Mediator leg/tail domain via the Med13 subunit, and this submodule–Mediator association precludes pol II recruitment. Collectively, these results reveal the CDK8 subcomplex functions as a simple switch that controls the Mediator–pol II interaction to help regulate transcription initiation and reinitiation events. As Mediator is generally required for expression of protein-coding genes, this may reflect a common mechanism by which activated transcription is shut down in human cells.
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Footnotes
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↵2 Corresponding author.
↵E-MAIL taatjes{at}colorado.edu; FAX (303) 492-5894.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1767009.
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Supplemental material is available at http://www.genesdev.org.
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- Received November 25, 2008.
- Accepted January 6, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press