Mediator kinases and Mediator kinase module
Our lab and others have shown that a four-subunit Mediator kinase module (MKM) can reversibly associate with the 26-subunit Mediator complex. The MKM is 600 kDa in size and consists of MED12, MED13, CDK8, and CCNC; also, the MKM composition can vary with subunit paralogs (see below). The MKM contains a kinase (CDK8 or CDK19) 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 Mediator kinases is sequence-specific DNA-binding transcription factors (TFs). Thus, just as TFs control Mediator function, the MKM controls TF function. Additionally, Mediator-MKM 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 both similar and distinct biological functions that remain to be characterized. Ongoing projects continue to examine how the MKM governs pol II transcription and cell signaling pathways. Mutations in MKM proteins are linked to many human diseases, and these are a focus of our studies as well. MKM subunits MED12 and MED13 also have paralogs in human cells (MED12L and MED13L) whose functions are poorly understood.
The Figure above shows a working model for how the MKM may function at human enhancer sequences. MKM 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 hubs or condensates, which is represented by green shading. MKM–Mediator binding cannot occur if Mediator is bound to pol II within the PIC (left); however, MKM–Mediator interaction may occur after pol II escapes the promoter and begins to transcribe (arrow, right). The MKM–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 MKM 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 MKM 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 is 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:
Cozzolino, K; Sanford, L; Hunter, S; Molison, K; Erickson, B; Courvan, MCS; Jones, T; Ajit, D; Galbraith, MG; Espinosa, JM; Bentley, DL; Allen, MA; Dowell, RD; Taatjes, DJ. Mediator kinase inhibition suppresses hyperactive interferon signaling in Down syndrome. eLife 2025, 13: RP100197.
Nussbaum, DP; Martz, CA; Waters, AM; Barrera, A; Liu, A; Rutter, JC; Cerda-Smith CG; Stewart, AE; Wu, C; Cakir, M; Levandowski, CB; Kantrowitz, DE; McCall, SJ; Pierobon, M; Petricoin, EF; Smith, JJ; Reddy, TE; Der, C; Taatjes, DJ; Wood, KC. Mediator kinase inhibition impedes transcriptional plasticity and prevents resistance to ERK/MAPK-targeted therapy in KRAS-mutant cancers. NPJ Precision Oncol 2024, 8: 124.
Maia-Silva, D; Cunniff, PJ; Schier, AC; Skopelitis, D; Trousdell, MC; Moresco, P; Gao, Y; Kechejian, V; He, X; Sahin, Y; Wan, L; Alpsoy, A; Liverpool, J; Krainer, AR; Egeblad, M; Spector, DL; Fearon, DT; Dos Santos, CO; Taatjes, DJ; Vakoc, CR. Interaction between MED12 and DNp63 activates basal identity in pancreatic ductal adenocarcinoma. Nat Genet 2024, 56: 1377 - 1385.
Johnson, JL; Yaron, TM; Huntsman, EM; Kerelsky, A; Song, J; Regev, A; Lin, T-Y; Liberatore, K; Cizin, DM; Cohen, BM; Vasan, N; Ma, Y; Krismer, K; Torres Robles, J; van de Kooij, B; van Klimmeren, AE; Andree-Busch, N; Kaufer, N; Dorovkov, MV; Ryazanov, AG; Takagi, Y; Kastenhuber, ER; Goncalves, MD; Hopkins, BD; Elemento, O; Taatjes, DJ; Maucuer, A; Yamashita, A; Degterev, A; Linding, R; Blenis, J; Hornbeck, PV; Turk, BE; Yaffe, MB; Cantley, LC. A global atlas of substrate specificities for the human serine/threonine kinome. Nature 2023, 613: 759 - 766.
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.