The CDK8 kinase module: A novel player in the transcription of translation initiation and ribosomal genes.

Abstract

Survival following stress is dependent upon reprogramming transcription and translation. Communication between these programs following stress is critical for adaptation but is not clearly understood. The Cdk8 kinase module (CKM) of the Mediator complex modulates the transcriptional response to various stresses. Its involvement in regulating translational machinery has yet to be elucidated, highlighting an existing gap in knowledge. Here, we report that the CKM positively regulates a subset of ribosomal protein (RP) and translation initiation factor (TIF)-encoding genes under physiological conditions in Saccharomyces cerevisiae. In mouse embryonic fibroblasts and HCT116 cells, the CKM regulates unique sets of RP and TIF genes, demonstrating some conservation of function across species. In yeast, this is mediated by Cdk8 phosphorylation of one or more transcription factors which control RP and TIF expression. Conversely, the CKM is disassembled following nutrition stress, permitting repression of RP and TIF genes. The CKM also plays a transcriptional role important for promoting cell survival, particularly during translational machinery stress triggered by ribosome-targeting antibiotics. Furthermore, in mammalian cells, the activity of CDK8 and its paralogue, CDK19, promotes cell survival following ribosome inhibition. These results provide mechanistic insights into the CKM's role in regulating expression of a subset of genes associated with translation.