The Pre-Initiation Complex (PIC), which consists of Mediator, TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH, and RNA polymerase II (pol II), governs the expression of all protein-coding and most non-coding RNA genes in the human genome and is approximately 4.0 MDa in size.  Mediator and TFIID, each approximately 1.4 MDa, represent major assemblies within the PIC and work to control PIC function in ways that are just beginning to be understood.  The structural features of Mediator and TFIID (conformationally dynamic, extended shape) coupled with their large size (e.g. human Mediator approximately 320 x 180 x 160 Å) provide an extensive surface for interaction with other proteins or nucleic acids.  TFIIH is also a large (10 subunit, 0.5MDa) and structurally dynamic protein complex.  Like Mediator and TFIID, TFIIH is required for pol II transcription, genome-wide.  Notably, Mediator, TFIID, and TFIIH appear to function cooperatively within the PIC; however, the molecular mechanisms underlying their coordinated or synergistic function remain poorly understood.   Our lab is using a variety of biochemical, cellular, and biophysical methods to better define how Mediator, TFIID, and TFIIH work together with other PIC components to regulate pol II transcription initiation, promoter-proximal pausing, and elongation.

PIC_pausing Fig_2021

Recent publications related to this topic:

Nayak, S; Taatjes DJ. SnapShot: Mediator Complex Structure. Cell 2022, 185: 3458.

Bassett, J; Rimel, JK; Basu, S; Basnet, P; Luo, J; Engel, KL; Nagel, MT; Woyciehowsky, A; Ebmeier, CC; Kaplan, CD; Taatjes, DJ; Ranish, JA. Systematic mutagenesis of TFIIH subunit p52/Tfb2 identifies residues required for XPB/Ssl2 subunit function and genetic interactions with TFB6. J Biol Chem 2022, 102433.

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.  

Palacio, M; Taatjes DJ. Merging established mechanisms with new insights: Condensates, hubs, and the regulation of RNA polymerase II transcription. J Mol Biol 2022, 433: 167216.  

Schier, A; Taatjes, DJ. Everything at once: Cryo-EM yields remarkable insights about human RNA polymerase II transcription. Nat Struct Mol Biol 2021, 28: 540 - 543.  

Tomko, EJ; Luyties, O; Rimel, JK; Tsai, C; Fuss, JO; Fishburn, J; Hahn, S; Tsutakawa, SE; Taatjes, DJ; Galburt, EA. The role of XPB/Ssl2 dsDNA translocation processivity in transcription start-site scanning. J Mol Biol 2021; 433: 166813.

Rimel, JK; Poss, ZC; Erickson, B; Maas, ZL; Ebmeier, CC; Johnson, JL; Decker, T-M; Yaron, TM; Bradley, MJ; Hamman, KB; Hu, S; Malojcic, G; Marineau, JJ; White, PW; Brault, M.; Tao, L.; DeRoy, P; Clavette, C; Nayak, S; Damon, LJ; Kaltheuner, IH; Bunch, H; Cantley, LC; Geyer, M; Iwasa, J; Dowell, RD; Bentley, DL; Old WM;* Taatjes, DJ.*  Selective inhibition of CDK7 reveals high-confidence targets and novel mechanisms for TFIIH function in transcription. Genes Dev 2020; 34: 1452 – 1473.

Fant, CB; Levandowski, CB; Gupta, K; Maas, ZL; Moir, JT; Rubin, JD; Sawyer, A; Esbin, M; Rimel, JK; Luyties, O; Marr, MT; Berger, I; Dowell, RD; Taatjes, DJ. TFIID enables RNA polymerase II promoter-proximal pausing. Mol Cell 2020, 78: 785 – 793. 

Schier, AC; Taatjes, DJ. Structure and mechanism of the RNA polymerase II transcription machinery. Genes Dev. 2020, 34: 465 – 488. 

Guo, YE; Manteiga, JC; Henninger, J; Sabari, BR; Dall'Agnese, A; Hannett, NM; Spille, J-H; Afeyan, LK; Zamudio, AV;  Shrinivas, K; Abraham, BJ; Boija, A; Decker, TM; Rimel, JK; Fant, CB; Lee, TI; Cisse, II; Sharp, PA; Taatjes, DJ; Young, RA. RNA polymerase II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature 2019, 572: 543 – 548.

Rimel, JK; Taatjes, DJ. The essential and multi-functional TFIIH complex. Protein Sci. 2018, 27: 1018 - 1037.  

Harper, TM; Taatjes, DJ.  The complex structure and function of Mediator. J Biol Chem.  2018, 293: 13778 - 13785.

Ebmeier, CC; Erickson, B; Allen, BL; Allen, MA; Kim, H; Fong, N; Jacobsen, JR; Liang, K; Shilatifard, A; Dowell, RD; Old, WM; Bentley, DL*; Taatjes, DJ*. Human TFIIH kinase CDK7 regulates transcription-associated chromatin modifications. Cell Rep.  2017, 20: 1173 - 1186.

Lerner, E; Chung, S; Allen, BL; Wang, S; Lee, JJ; Lu, SW; Grimaud, LW; Ingargiola, A; Michalet, X; Alhadid, Y; Borukhov, S; Strick, T;* Taatjes, DJ;* Weiss, S.* A backtracked and paused transcription initiation intermediate of Escherichia Coli RNA polymerase. Proc Natl Acad Sci. USA. 2016, 113: E6562 – E6571.

Luo, J; Cimermancic, P; Viswanath, S; Ebmeier, CC; Kim, B; Dehecq, M; Raman, V; Sali, A; Taatjes, DJ; Hahn, S; Ranish, J. Architecture of the human and yeast general transcription and DNA repair factor TFIIH. Mol Cell 2015, 59: 794 – 806.

Allen, BL; Taatjes, DJ. The Mediator complex: a central integrator of transcription. Nat Rev Mol Cell Biol.  2015, 16: 155 – 166.  

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