CDK8 and CDK19 cooperate to control responses to oxidative stress in primary vertebrate cells: Mediator kinases control stress

The mammalian Mediator transcription complex kinase module contains one of two cyclindependent kinase (CDK) paralogues, CDK8 or CDK19. Whether they are functionally redundant or each control specific genes is debated, and the mechanisms by which they affect cell physiology remain unclear. We show, using primary murine embryonic fibroblasts (MEFs), that CDK8 and CDK19 have both overlapping and opposing effects on gene expression, with only minor effects of knockout of either kinase alone. In contrast, double knockout (DKO) MEFs have genome-scale transcriptome alterations, indicating that most of their target genes can be controlled by either kinase. DKO MEFs, or MEFs treated with CDK8/19 inhibitors, are viable but proliferate slowly. DKO or CDK8/19iinhibited MEFs show transcriptional alterations similar to those of wild-type MEFs treated with a variety of chemical oxidative stress inducers or UV irradiation. Furthermore, DKO MEFs are sensitized to such stress, in accordance with their altered expression of p53dependent apoptotic regulatory genes. Our results suggest that the two Mediator kinases control most expressed genes in a primary differentiated cell type and buffer transcriptional responses to oxidative stress.

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