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听MDa in size. 听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. 听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 脜) provide an extensive surface for interaction with other proteins or nucleic acids. 听TFIIH is also a large (10 subunit, 0.5MDa) and structurally dynamic protein complex. 听Like Mediator and TFIID, TFIIH is required for pol II transcription, genome-wide. 听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. 听 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.
Recent publications related to this topic:
Nayak, S; Taatjes DJ. SnapShot: Mediator Complex Structure.听Cell听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.听J Biol Chem听2022, 102433.
Richter, WF; Nayak, S; Iwasa, J; Taatjes, DJ. The Mediator complex as a master regulator of transcription by RNA polymerase II.听Nat Rev Mol Cell Biol听2022, 23: 732 - 749.
Luyties, O; Taatjes, DJ.听听The Mediator kinase module: an interface between cell signaling and transcription.听Trends Biochem Sci听2022, 47: 314 - 327.听听
Palacio, M; Taatjes DJ.听Merging established mechanisms with new insights: Condensates, hubs, and the regulation of RNA polymerase II transcription.听J Mol Biol听2022, 433: 167216.听听
Schier, A; Taatjes, DJ.听Everything at once: Cryo-EM yields remarkable insights about human RNA polymerase II transcription.听Nat Struct Mol Biol听2021, 28: 540 - 543.听听
Tomko, EJ; Luyties, O; Rimel, JK; Tsai, C; Fuss, JO; Fishburn, J; Hahn, S; Tsutakawa, SE; Taatjes, DJ; Galburt, EA.听The role of XPB/Ssl2 dsDNA translocation processivity in transcription start-site scanning.听J Mol Biol听2021;听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.*听听Selective inhibition of CDK7 reveals high-confidence targets and novel mechanisms for TFIIH function in transcription.听Genes Dev听2020; 34: 1452 鈥撎�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.听Mol Cell听2020, 78: 785 鈥� 793.听
Schier, AC; Taatjes, DJ. Structure and mechanism of the RNA polymerase II transcription machinery.听Genes Dev.听2020, 34: 465 鈥� 488.听
Guo, YE; Manteiga, JC; Henninger, J; Sabari, BR; Dall'Agnese, A; Hannett, NM; Spille, J-H; Afeyan, LK; Zamudio, AV;听听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.听Nature听2019, 572: 543 鈥� 548.
Rimel, JK; Taatjes, DJ. The essential and multi-functional TFIIH complex.听Protein Sci.听2018, 27: 1018 - 1037.听听
Harper, TM; Taatjes, DJ.听听The complex structure and function of Mediator.听J Biol Chem.听听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. 听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 鈥� 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 鈥� 806.
Allen, BL; Taatjes, DJ. The Mediator complex: a central integrator of transcription.听Nat Rev Mol Cell Biol.听听2015, 16: 155 鈥撎�166.听听