Direct RNA-binding by MYCN mediates feedback from RNA processing to transcription control
Papadopoulos, D.; Ha, S. A.; Fleischhauer, D.; Uhl, L.; Schneider, K.; Mikicic, I.; Russell, T. J.; Brem, A.; Valanju, O. R.; Gallant, P.; Schuelein-Voelk, C.; Maric, H. M.; Beli, P.; Buechel, G.; Vos, S. M.; Eilers, M.
Show 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.
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