Publications
bioRxivAug 2023 DOI:
10.1101/2023.08.16.553474

Direct RNA-binding by MYCN mediates feedback from RNA processing to transcription control

Papadopoulos, Dimitrios; Ha, Stefanie Anh; Fleischhauer, Daniel; Uhl, Leonie; Schneider, Katharina; Mikicic, Ivan; Russell, Timothy J.; Brem, Annika; Valanju, Omkar Rajendra; Gallant, Peter; Schuelein-Voelk, Christina; Maric, Hans Michael; Beli, Petra; Büchel, Gabriele; Vos, Seychelle M.; Eilers, Martin
Product Used
Genes
Abstract
The MYCN oncoprotein broadly 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. In cells, MYCN binds to thousands of intronic RNAs; recombinant MYCN directly binds RNA via a short, highly conserved sequence termed MYCBoxI. Perturbing exosome function results in global re-localization of MYCN from promoters to intronic RNAs. At promoters, MYCN is then replaced by the MNT(MXD6) repressor protein, which inhibits MYCN-dependent transcription. MYCN promotes the degradation of its bound introns via the nuclear exosome targeting (NEXT) complex. Our data demonstrate that MYCN is an RNA-binding protein that regulates nascent transcript turnover and show that competition between its RNA- and DNA-bound states links the dynamics of the MYCN/MAX/MXD network to mRNA processing.
Product Used
Genes

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