Regulatory mechanisms of transcription-associated kinases
RNA Polymerase II (Pol II) activity is regulated by many factors to ensure that transcription is conducted precisely and efficiently. Three of these factors are known as transcriptional kinases: CDK7, CDK8, and CDK9. Each of these kinases functions within multi-subunit complexes TFIIH, the CDK8 module, and P-TEFb, respectively. Together, these kinases help orchestrate a series of phosphorylation events that control Pol II transcription initiation, pausing, and elongation. Many aggressive cancers have been found to be “addicted” to these kinases, highlighting their importance in cancer biology. Still, we have not yet characterized the roles of these kinases in transcription to the fullest extent. My project focuses on elucidating the biochemical mechanisms through which each of the transcriptional kinases regulates Pol II transcription using our human in vitro transcription system which is reconstituted from purified factors. I am further testing mechanistic findings through targeted cell-based methods that involve genome editing, pharmacological inhibitors, and transcriptomics.
Publications
Luyties, O; Taatjes, DJ. The Mediator kinase module: an interface between cell signaling and transcription. Trends Biochem Sci 2022, 47: 314 - 327.
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.
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.
Walker, JE; Luyties, O; Santangelo, TJ. Factor-dependent archaeal transcription termination. PNAS 2017, 114: E6767 – E6773. [PMID: 28760969]