Our lab and others have shown that a four-subunit CDK8 module can reversibly associate with the 26-subunit Mediator complex. The CDK8 module is 600 kDa in size and consists of MED12, MED13, CDK8, and CCNC. The CDK8 module acts as a kinase (CDK8) and likely functions on its own, as well as when associated with Mediator, as the so-called “CDK8-Mediator” complex.
A major class of proteins phosphorylated by CDK8 is sequence-specific DNA-binding transcription factors (TFs). Thus, just as TFs control Mediator function, CDK8 controls TF function. Additionally, Mediator-CDK8 module interaction blocks Mediator-pol II binding, which likely regulates transcription initiation or re-initiation events at the promoter. A paralog of CDK8, called CDK19, emerged in vertebrates and appears to have adopted distinct biological functions that remain to be characterized. Ongoing projects continue to examine how the CDK8 module (or the CDK19 module) governs pol II transcription and cell signaling pathways. Mutations in CDK8 module proteins are linked to many human diseases, and these are a focus of our studies as well.
The Figure above shows a working model for how CDK8 or CDK19 modules may function at human enhancer sequences. CDK8 (or CDK19) module association with an enhancer (e.g. via TF binding) could allow interaction with promoters that are juxtaposed via enhancer-promoter chromatin loops. This co-localization may be facilitated by eRNA transcription and/or liquid-liquid phase separation (LLPS), which is represented by green shading. CDK8/19 module–Mediator binding cannot occur if Mediator is bound to pol II within the PIC (left); however, CDK8 module–Mediator interaction may occur after pol II escapes the promoter and begins to transcribe (arrow, right). The CDK8 module–Mediator interaction would prevent re-initiation by another pol II complex, and this may serve as a means to shut off transcriptional bursting (right). The CDK8 module can also regulate pol II pausing and elongation, perhaps through phosphorylation of NELF or cooperative interactions with the Super-Elongation Complex (not shown) or other factors. It remains unclear whether the CDK8 module (or CDK19 module) performs these functions only when bound to Mediator, or whether some functions may result from the module acting independently. At right, transcriptional bursting is depicted, in which multiple pol II complexes initiate from the same promoter in rapid succession, followed by extended dormant periods. This process appears to be Mediator-dependent, but the mechanisms that control bursting and pol II re-initiation remain unclear. Note that promoter-proximal termination of transcription can also occur, as an alternative to pol II pause release and elongation (dashed arrow).
Recent publications related to this topic:
Clopper, KC; Taatjes, DJ. Chemical inhibitors of transcription-associated kinases. Curr Opin Chem Biol 2022, 70: 102186.
Richter, WF; Nayak, S; Iwasa, J; Taatjes, DJ. The Mediator complex as a master regulator of transcription by RNA polymerase II. Nat Rev Mol Cell Biol 2022, 23: 732 - 749.
Luyties, O; Taatjes, DJ. The Mediator kinase module: an interface between cell signaling and transcription. Trends Biochem Sci 2022, 47: 314 - 327.
Steinparzer, I; Sedlyarov, V; Rubin, JD; Eislmayr, K; Galbraith MD; Levandowski, CB; Vcelkova, T; Sneezum, L; Wascher, F; Amman, F; Kleinova, R; Bender, H; Andrysik, Z; Espinosa, JM; Superti-Furga, G; Dowell, RD; Taatjes, DJ;* Kovarik, P.* Transcriptional responses to IFNg require Mediator kinase-dependent pause release and mechanistically distinct CDK8 and CDK19 functions. Mol Cell 2019, 76: 485 – 499.
Fant, CB; Taatjes, DJ. Regulatory functions of the Mediator kinases CDK8 and CDK19. Transcription 2019, 10: 76 – 90.
Harper, TM; Taatjes, DJ. The complex structure and function of Mediator. J Biol Chem. 2018, 293: 13778 - 13785.
Audetat, KA; Galbraith, MD; Odell, AT; Lee, T; Pandey, A; Espinosa, JM; Dowell, RD; Taatjes, DJ. A kinase-independent role for CDK19 in p53 response. Mol Cell Biol. 2017, 37: e00626-16.
Poss, ZC; Ebmeier, CC; Odell, AT; Tangpeerachaikul, A; Lee, T; Pelish, HE; Shair, MD; Dowell, RD; Old, WM; Taatjes, DJ. Identification of Mediator kinase substrates in human cells using cortistatin A and quantitative phosphoproteomics. Cell Rep. 2016, 15: 436 – 450.
Pelish, HE; Liau, BB; Nitulescu, I; Tangpeerachaikul, A; Poss, ZC; DaSilva, D; Caruso, B; Arefolov, A; Fadeyi, O; Christie, A; Du, K; Banka, D; Schneider, EV; Jestel, A; Zou, G; Si, C; Ebmeier, CC; Bronson, RT; Krivtsov, AV; Myers, AG; Kohl, N; Kung, A; Armstrong, S; Lemieux, M; Taatjes, DJ; Shair, MD. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature 2015, 526: 273 – 276.