MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription replication conflicts

Published: 16 December 2021| Version 1 | DOI: 10.17632/rc6rfg45n5.1
Dimitrios Papadopoulos,


The MYCN oncoprotein drives the development of numerous neuroendocrine and pediatric tumors. Here we show that MYCN interacts with the nuclear RNA exosome, a 3'-5' exoribonuclease complex, and recruits the exosome to its target genes. In the absence of the exosome, MYCN-directed elongation by RNA Polymerase II (RNAPII) is slow and non-productive on a large group of cell cycle-regulated genes. During the S phase of MYCN-driven tumor cells, the exosome is required to prevent the accumulation of stalled replication forks and of double-strand breaks close to the transcription start sites. Upon depletion of the exosome, activation of ATM causes recruitment of BRCA1, which stabilizes nuclear mRNA decapping complexes, leading to MYCN-dependent transcription termination. Disruption of mRNA decapping in turn activates ATR, indicating transcription-replication conflicts. We propose that exosome recruitment by MYCN maintains productive transcription elongation during S-phase and prevents transcription-replication conflicts to maintain the rapid proliferation of neuroendocrine tumor cells.



Julius-Maximilians-Universitat Wurzburg


Transcription, Neuroblastoma, DNA Damage Response, Exosome