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The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function.

Genes & development | Feb 15, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19240132

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.

Pubmed ID: 19240132 RIS Download

Mesh terms: Chromatin | Cyclin-Dependent Kinase 8 | Cyclin-Dependent Kinases | DNA Polymerase II | Gene Expression Regulation | Humans | Mediator Complex | Protein Binding | Recombinant Proteins | Transcription Factors

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Associated grants

  • Agency: NCI NIH HHS, Id: P01 CA112181
  • Agency: NIGMS NIH HHS, Id: T32 GM065103
  • Agency: NIGMS NIH HHS, Id: T32 GM07135

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