MYCN is an RNA-binding accessory protein of the nuclear exosome

The MYCN oncoprotein broadly binds promoters in a heterodimer with its partner protein MAX. MYCN also interacts with the nuclear exosome, a 3’-5’exoribonuclease complex, to facilitate progression through the S phase hinting at an RNA-centric function. Here we show that MYCN forms stable high molecular weight complexes with multiple RNA-binding proteins including the nuclear exosome. RNA-binding assays reveal that MYCN directly binds to thousands of predominantly intronic RNA sites via a short, highly conserved sequence motif termed MYCBoxI. Exosome depletion results in MYCN globally re-localizing from promoters to intronic RNAs. The vacant promoters are then occupied by the MXD transcription repressor protein MNT, which inhibits MYCN-dependent transcription. MYCN fosters the degradation of its bound introns via tight association with the nuclear exosome targeting complex (NEXT). Our data demonstrate that MYCN is an RNA-binding protein that controls RNA turnover and argue that the competition between MYCN’s RNA- and DNA-bound states links the dynamics of the MYCN/MAX/MXD network to mRNA processing.