MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Elsevier BV
2023
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| Online Access: | https://hdl.handle.net/1721.1/147120 |
| _version_ | 1811078757675433984 |
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| author | Papadopoulos, Dimitrios Solvie, Daniel Baluapuri, Apoorva Endres, Theresa Ha, Stefanie Anh Herold, Steffi Kalb, Jacqueline Giansanti, Celeste Schülein-Völk, Christina Ade, Carsten Patrick Schneider, Cornelius Gaballa, Abdallah Vos, Seychelle Fischer, Utz Dobbelstein, Matthias Wolf, Elmar Eilers, Martin |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Papadopoulos, Dimitrios Solvie, Daniel Baluapuri, Apoorva Endres, Theresa Ha, Stefanie Anh Herold, Steffi Kalb, Jacqueline Giansanti, Celeste Schülein-Völk, Christina Ade, Carsten Patrick Schneider, Cornelius Gaballa, Abdallah Vos, Seychelle Fischer, Utz Dobbelstein, Matthias Wolf, Elmar Eilers, Martin |
| author_sort | Papadopoulos, Dimitrios |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T11:05:03Z |
| format | Article |
| id | mit-1721.1/147120 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:05:03Z |
| publishDate | 2023 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1471202024-02-05T18:15:20Z MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts Papadopoulos, Dimitrios Solvie, Daniel Baluapuri, Apoorva Endres, Theresa Ha, Stefanie Anh Herold, Steffi Kalb, Jacqueline Giansanti, Celeste Schülein-Völk, Christina Ade, Carsten Patrick Schneider, Cornelius Gaballa, Abdallah Vos, Seychelle Fischer, Utz Dobbelstein, Matthias Wolf, Elmar Eilers, Martin Massachusetts Institute of Technology. Department of Biology 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. 2023-01-17T14:23:40Z 2023-01-17T14:23:40Z 2022 2023-01-17T14:18:29Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/147120 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). en 10.1016/J.MOLCEL.2021.11.002 Molecular Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV Prof. Seychelle Vos |
| spellingShingle | Papadopoulos, Dimitrios Solvie, Daniel Baluapuri, Apoorva Endres, Theresa Ha, Stefanie Anh Herold, Steffi Kalb, Jacqueline Giansanti, Celeste Schülein-Völk, Christina Ade, Carsten Patrick Schneider, Cornelius Gaballa, Abdallah Vos, Seychelle Fischer, Utz Dobbelstein, Matthias Wolf, Elmar Eilers, Martin MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts |
| title | MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts |
| title_full | MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts |
| title_fullStr | MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts |
| title_full_unstemmed | MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts |
| title_short | MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription-replication conflicts |
| title_sort | mycn recruits the nuclear exosome complex to rna polymerase ii to prevent transcription replication conflicts |
| url | https://hdl.handle.net/1721.1/147120 |
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