The MYCN oncoprotein is an RNA-binding accessory factor of the nuclear exosome targeting complex

Dimitrios Papadopoulos; Stefanie Anh Ha; Daniel Fleischhauer; Leonie Uhl; Timothy J Russell; Ivan Mikicic; Katharina Schneider; Annika Brem; Omkar Rajendra Valanju; Giacomo Cossa; Peter Gallant; Christina Schuelein-Voelk; Hans Michael Maric; Petra Beli; Gabriele Büchel; Seychelle M Vos; Martin Eilers

doi:10.1016/j.molcel.2024.04.007

The MYCN oncoprotein is an RNA-binding accessory factor of the nuclear exosome targeting complex

Mol Cell. 2024 Apr 26:S1097-2765(24)00285-5. doi: 10.1016/j.molcel.2024.04.007. Online ahead of print.

Authors

Dimitrios Papadopoulos¹, Stefanie Anh Ha², Daniel Fleischhauer², Leonie Uhl², Timothy J Russell³, Ivan Mikicic⁴, Katharina Schneider³, Annika Brem³, Omkar Rajendra Valanju⁵, Giacomo Cossa², Peter Gallant², Christina Schuelein-Voelk⁶, Hans Michael Maric⁵, Petra Beli⁴, Gabriele Büchel¹, Seychelle M Vos⁷, Martin Eilers⁸

Affiliations

¹ Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany; Mildred Scheel Early Career Center, University Hospital Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany.
² Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
³ Massachusetts Institute of Technology, Department of Biology, 31 Ames Street, Cambridge, MA 02142, USA.
⁴ Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg University, Ackermannweg 4, 55128 Mainz, Germany; Institute of Molecular Biology (IMB), Johannes Gutenberg University, Ackermannweg 4, 55128 Mainz, Germany.
⁵ Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Josef-Schneider-Str. 2, Building D15, 97080 Würzburg, Germany.
⁶ Theodor Boveri Institute, Core Unit High-Content Microscopy, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
⁷ Massachusetts Institute of Technology, Department of Biology, 31 Ames Street, Cambridge, MA 02142, USA. Electronic address: seyvos@mit.edu.
⁸ Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. Electronic address: martin.eilers@uni-wuerzburg.de.

PMID: 38703770
DOI: 10.1016/j.molcel.2024.04.007

Abstract

The MYCN oncoprotein binds active promoters in a heterodimer with its partner protein MAX. MYCN also interacts with the nuclear exosome, a 3'-5' exoribonuclease complex, suggesting a function in RNA metabolism. Here, we show that MYCN forms stable high-molecular-weight complexes with the exosome and multiple RNA-binding proteins. MYCN binds RNA in vitro and in cells via a conserved sequence termed MYCBoxI. In cells, MYCN associates with thousands of intronic transcripts together with the ZCCHC8 subunit of the nuclear exosome targeting complex and enhances their processing. Perturbing exosome function results in global re-localization of MYCN from promoters to intronic RNAs. On chromatin, MYCN is then replaced by the MNT(MXD6) repressor protein, inhibiting MYCN-dependent transcription. RNA-binding-deficient alleles show that RNA-binding limits MYCN's ability to activate cell growth-related genes but is required for MYCN's ability to promote progression through S phase and enhance the stress resilience of neuroblastoma cells.

Keywords: MAX; MNT; MXD; MYC; MYCN; NEXT; ZCCHC8; exosome; neuroblastoma.