Markus Dehmer1,2,13, Katrin Trunk1,13, Peter Gallant1, Daniel Fleischhauer1, Mareike Müller1,2, Steffi Herold1, Giacomo Cossa1, Francesca Conte3, Jan Koster4, Florian Sauer5, Christina Schülein-Völk6, Carsten P. Ade1, Raphael Vidal1,7,12, Caroline Kisker5, Rogier Versteeg8, Petra Beli3,9, Seychelle M. Vos10,11, Martin Eilers1,7 and Gabriele Büchel1,2,7 1Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, 97074 Würzburg, Germany; 2Mildred Scheel Early Career Center, University Hospital Würzburg, 97080 Würzburg, Germany; 3Institute of Molecular Biology (IMB), Johannes Gutenberg University, 55128 Mainz, Germany; 4Applied Bioinformatics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; 5Rudolf-Virchow-Center for Integrative and Translational Imaging, University of Würzburg, 97080 Würzburg, Germany; 6Theodor Boveri Institute, Core Unit High-Content Microscopy, Biocenter, University of Würzburg, 97074 Würzburg, Germany; 7Comprehensive Cancer Center Mainfranken, 97080 Würzburg, Germany; 8Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin, 10117 Berlin, Germany; 9Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg University, 55128 Mainz, Germany; 10Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA; 11Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA Corresponding authors: gabriele.buecheluni-wuerzburg.de, martin.eilersuni-wuerzburg.de

↵13 These authors contributed equally to this work.

↵12 Present address: Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.

Abstract

During early transcription, RNA polymerase II (RNAPII) undergoes a series of structural transitions controlled by cyclin-dependent kinases. How protein ubiquitylation and proteasomal degradation control the function of RNAPII is less well understood. Here we show that the deubiquitinating enzyme USP11 forms a complex with TCEAL1, a member of the TFIIS (TCEA)-like protein family. TCEAL1 shares sequence homology with the RNAPII interaction domain of the elongation factor TFIIS (which controls the fate of backtracked RNAPII) and competes with TFIIS for binding to core promoters. USP11 protects TCEAL1 from proteasomal degradation, and TCEAL1 recruits USP11 to RNAPII. Both USP11 and TCEAL1 promote transcription elongation and maintain expression of RPB8, an essential subunit of all three nuclear RNA polymerases. In neuroblastoma, USP11- and TCEAL1-dependent genes define a gene expression program that is characteristic for mesenchymal tumors, which are described as able to escape from many treatments, suggesting that the USP11/TCEAL1 complex promotes transcription elongation to support a critical oncogenic gene expression program.

Received July 29, 2024. Accepted March 19, 2025.