MYC Recruits SPT5 to RNA Polymerase II to Promote Processive Transcription Elongation.

Robert Düster, Elmar Wolf, Martin Eilers, Patrick Cramer, Andreas Schlosser, Susanne Walz, Peter Gallant, Hans Michael Maric, Matthias Geyer, Armin Wiegering, Jens Thorsten Vanselow, Lisa Anna Jung, Apoorva Baluapuri, Shuang-Yan Wang, Markus Vogt, Ashwin Narain, Jessica Denise Schwarz, Bikash Adhikari, Seychelle Monique Vos, Pranjali Bhandare, Theresa Endres, Nevenka Dudvarski Stankovic, Julia Hofstetter

Journal: Molecular cell 2019;74(4):674-687.e11

PMID: 30928206

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Abstract

The MYC oncoprotein binds to promoter-proximal regions of virtually all transcribed genes and enhances RNA polymerase II (Pol II) function, but its precise mode of action is poorly understood. Using mass spectrometry of both MYC and Pol II complexes, we show here that MYC controls the assembly of Pol II with a small set of transcription elongation factors that includes SPT5, a subunit of the elongation factor DSIF. MYC directly binds SPT5, recruits SPT5 to promoters, and enables the CDK7-dependent transfer of SPT5 onto Pol II. Consistent with known functions of SPT5, MYC is required for fast and processive transcription elongation. Intriguingly, the high levels of MYC that are expressed in tumors sequester SPT5 into non-functional complexes, thereby decreasing the expression of growth-suppressive genes. Altogether, these results argue that MYC controls the productive assembly of processive Pol II elongation complexes and provide insight into how oncogenic levels of MYC permit uncontrolled cellular growth.

Address: Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.; Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.; Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.; Rudolf Virchow Center for Experimental Biomedicine, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.; Institute of Structural Biology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.; Karolinska Institutet, Department of Biosciences and Nutrition, Hälsovägen 7C, 14157 Huddinge, Sweden.; Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany; Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.; Core Unit Bioinformatics, Comprehensive Cancer Center Mainfranken, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.; Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany; Karolinska Institutet, Department of Biosciences and Nutrition, Hälsovägen 7C, 14157 Huddinge, Sweden.; Cancer Systems Biology Group, Theodor Boveri Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. Electronic address: [email protected].

DOI: 10.1016/j.molcel.2019.02.031