MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts
Name
Papadopoulos et al.pdf
Description
Accepted version
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8.96 MB
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Checksum (MD5)
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Author(s)
Papadopoulos, Dimitrios
Solvie, Daniel
Baluapuri, Apoorva
Endres, Theresa
Ha, Stefanie Anh
Herold, Steffi
Kalb, Jacqueline
Giansanti, Celeste
Schülein-Völk, Christina
Ade, Carsten Patrick
Date Issued
2022
Journal
Molecular Cell
Publisher
Elsevier BV
Citation
Papadopoulos, Dimitrios, Solvie, Daniel, Baluapuri, Apoorva, Endres, Theresa, Ha, Stefanie Anh et al. 2022. "MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts." Molecular Cell, 82 (1).
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.MOLCEL.2021.11.002
