Knuesel, Matthew; Meyer, Krista; Bernecky, CarrieIST Austria ; Taatjes, Dylan
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.
Genes and Development
439 - 451
Knuesel M, Meyer K, Bernecky C, Taatjes D. The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function. Genes and Development. 2009;23(4):439-451. doi:10.1101/gad.1767009
Knuesel, M., Meyer, K., Bernecky, C., & Taatjes, D. (2009). The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function. Genes and Development, 23(4), 439–451. https://doi.org/10.1101/gad.1767009
Knuesel, Matthew, Krista Meyer, Carrie Bernecky, and Dylan Taatjes. “The Human CDK8 Subcomplex Is a Molecular Switch That Controls Mediator Coactivator Function.” Genes and Development 23, no. 4 (2009): 439–51. https://doi.org/10.1101/gad.1767009.
M. Knuesel, K. Meyer, C. Bernecky, and D. Taatjes, “The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function,” Genes and Development, vol. 23, no. 4, pp. 439–451, 2009.
Knuesel M, Meyer K, Bernecky C, Taatjes D. 2009. The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function. Genes and Development. 23(4), 439–451.
Knuesel, Matthew, et al. “The Human CDK8 Subcomplex Is a Molecular Switch That Controls Mediator Coactivator Function.” Genes and Development, vol. 23, no. 4, Cold Spring Harbor Laboratory Press, 2009, pp. 439–51, doi:10.1101/gad.1767009.
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