TFIIH and transcription regulation
Human TFIIH is a 10-subunit general transcription factor essential for RNA polymerase II (pol II) transcription. TFIIH is highly conserved and contains two helicases, XPB and XPD, and a kinase, cyclin-dependent kinase 7 (CDK7). The helicases are vital for “melting” double-stranded DNA for transcription as well as for nucleotide excision repair. CDK7 is important for regulating pol II transcription, RNA processing, and the cell cycle. Given these crucial roles of TFIIH, it comes as no surprise that its misregulation is associated with a variety of cancers and developmental diseases including triple negative breast cancer, T-cell lymphomas, xeroderma pigmentosum, cockayne syndrome, and trichothiodystrophy. My projects focus on the XPB helicase and CDK7 kinase of TFIIH, using a combination of in vitro and cell-based methods.
Publications
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.
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.
Boija, A; Klein, IA; Sabari, BR; Dall'Agnese, A; Coffey, EL; Zamudio, AV; Li, CH; Shrinivas, K; Manteiga, J; Hannett, NM; Abraham, BJ; Schuijers, J; Afeyan, L; Guo, YE; Rimel, JK; Fant, CB; Lee, TI; Taatjes, DJ;* Young, RA.* Transcription factors activate genes through the phase separation capacity of their activation domains. Cell 2018, 175: 1842 – 1855.
Rimel, JK; Taatjes DJ. The essential and multifunctional TFIIH complex. Protein Sci. 2018, 27: 1018-1037.
Schultz, VL; Zhang, X; Linkens, K; Rimel, J; Green DE; DeAngelis, PL; Linhardt, RJ. Chemoenzymatic synthesis of 4-fluoro-N-acetylhexosamin uridine diphosphate donors: chain terminators in glycosaminoglycan synthesis. J Org Chem. 2017, 82: 2243 - 2248. [PMID: 28128958]