The Mediator Kinase Module regulates cell cycle re-entry and transcriptional responses following DNA damage.

The Cdk8 kinase module (CKM) is a non-obligate and dissociable subcomplex of Mediator of transcription, a key regulator of RNA polymerase II (RNAPII). Through a genetic screen in yeast, we discovered a surprising role for Mediator CKM in the DNA damage response (DDR) and mitotic re-entry. Remarkably, we find that a single DNA break is sufficient for CKM-dependent global transcriptional attenuation. Upon DDR activation, the kinase activity of CKM antagonizes RNAPII binding to core Mediator, thereby reducing the transcriptionally-engaged RNAPII pool. This transcriptional attenuation is essential for DDR inactivation and limits the spreading of γ-H2AX into gene bodies. Furthermore, CKM localizes to DNA breaks to impede RNAPII binding. Importantly, we demonstrate that the role of CKM on DDR and transcriptional attenuation is conserved from yeast to mammals, establishing a multifaceted and essential function for CKM in transcriptional regulation of DNA-damage response.