Abstract
The Cdk8 kinase module (CKM) is a detachable Mediator subunit composed of cyclin C and one each of paralogs Cdk8/Cdk19, Med12/Med12L, and Med13/Med13L. Our previous RNA-Seq studies demonstrated that cyclin C represses a subset of hydrogen peroxide-induced genes under normal conditions but is involved in activating other loci following stress. Here, we show that cyclin C directs this transcriptional reprograming through changes in its promoter occupancy. Following peroxide stress, cyclin C promoter occupancy increased for genes it activates while decreasing at loci it represses under normal conditions. Promoter occupancy of other CKM components generally mirrored cyclin C, indicating that the CKM moves as a single unit. It has previously been shown that some cyclin C leaves the nucleus following cytotoxic stress to induce mitochondrial fragmentation and apoptosis. We observed that CKM integrity appeared compromised at a subset of repressed promoters, suggesting a source of cyclin C that is targeted for nuclear release. Interestingly, mTOR inhibition induced a new pattern of cyclin C promoter occupancy indicating that this control is fine-tuned to the individual stress. Using inhibitors, we found that Cdk8 kinase activity is not required for CKM movement or repression but was necessary for full gene activation. In conclusion, this study revealed that different stress stimuli elicit specific changes in CKM promoter occupancy correlating to altered transcriptional outputs. Finally, although CKM components were recruited or expelled from promoters as a unit, heterogeneity was observed at individual promoters, suggesting a mechanism to generate gene- and stress-specific responses.
Highlights
Cells exhibit multiple adaptive responses following exposure to cytotoxic agents
We found that cyclin C represses steady state transcription of genes that are induced by H2O2 treatment [7]
Using the Cdk8 kinase module (CKM) component cyclin C as a probe to monitor promoter occupancy, we examined both activated and repressed loci that respond to two stressors, H2O2-induced oxidative stress and starvation through mammalian target of rapamycin (mTOR) inhibition
Summary
Cells exhibit multiple adaptive responses following exposure to cytotoxic agents. The failure to mitigate the cellular damage caused by these stressors can initiate regulated cell death (RCD) pathways [1]. Following H2O2 exposure, promoter occupancy patterns of the CKM members generally mirrored that observed for cyclin C for each of the induced genes Trp53inp1, p21, Gabarap, and Adrm1 (Fig. 2A). For the repressed genes Jmy and Gtf2h1, there was a significant decrease in promoter occupancy of each CKM member in response to oxidative stress similar to that observed for cyclin C (Fig. 2B).
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