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

Genes Dev. 2009 Feb 15;23(4):439-51. doi: 10.1101/gad.1767009.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin / metabolism
  • Cyclin-Dependent Kinase 8
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • DNA Polymerase II / metabolism
  • Gene Expression Regulation*
  • Humans
  • Mediator Complex
  • Protein Binding
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Chromatin
  • MED12 protein, human
  • MED13 protein, human
  • Mediator Complex
  • Recombinant Proteins
  • Transcription Factors
  • CDK8 protein, human
  • Cyclin-Dependent Kinase 8
  • Cyclin-Dependent Kinases
  • DNA Polymerase II