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

ABSTRACT: 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 an

SUBMITTER: Memisoglu G 

PROVIDER: S-EPMC12139960 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature