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

Author:

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 MartinORCID

Abstract

AbstractThe 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.

Publisher

Cold Spring Harbor Laboratory

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