Senataxin prevents replicative stress induced by the Myc oncogene
Abstract Replicative stress (RS) is emerging as a promising therapeutic target in oncology, yet full exploitation of its potential requires a detailed understanding of the mechanisms and genes involved. Here, we investigated the RNA helicase Senataxin (SETX), an enzyme that resolves RNA-DNA hybrids...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-03-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07485-4 |
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| author | Silvia Sberna Marco Filipuzzi Nicola Bianchi Ottavio Croci Federica Fardella Chiara Soriani Sara Rohban Sara Carnevali Alessandra Alberta Albertini Nicola Crosetto Simona Rodighiero Arianna Chiesa Laura Curti Stefano Campaner |
| author_facet | Silvia Sberna Marco Filipuzzi Nicola Bianchi Ottavio Croci Federica Fardella Chiara Soriani Sara Rohban Sara Carnevali Alessandra Alberta Albertini Nicola Crosetto Simona Rodighiero Arianna Chiesa Laura Curti Stefano Campaner |
| author_sort | Silvia Sberna |
| collection | DOAJ |
| description | Abstract Replicative stress (RS) is emerging as a promising therapeutic target in oncology, yet full exploitation of its potential requires a detailed understanding of the mechanisms and genes involved. Here, we investigated the RNA helicase Senataxin (SETX), an enzyme that resolves RNA-DNA hybrids and R-loops, to address its role in preventing RS by oncogenic Myc. Upon Myc activation, silencing of SETX led to selective engagement of the DNA damage response (DDR) and robust cytotoxicity. Pharmacological dissection of the upstream kinases regulating the DDR uncovered a protective role of the ATR pathway, that once inhibited, boosted SETX driven-DDR. While SETX loss did not lead to a genome-wide increase of R-loops, mechanistic analyses revealed enhanced R-loops localized at DDR-foci and newly replicated genomic loci, compatible with a selective role of SETX in resolving RNA-DNA hybrids to alleviate Myc-induced RS. Genome-wide mapping of DNA double-strand breaks confirmed that SETX silencing exacerbated DNA damage at transcription-replication conflict (TRC) regions at early replicated sites. We propose that SETX prevents Myc-induced TRCs by resolving transcription-associated R-loops that encounter the replisome. The identification of SETX as a genetic liability of oncogenic Myc opens up new therapeutic options against aggressive Myc-driven tumors. |
| format | Article |
| id | doaj-art-c308e1775b2f41efb16ebfc38b8f9ac2 |
| institution | DOAJ |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-c308e1775b2f41efb16ebfc38b8f9ac22025-08-20T03:10:32ZengNature Publishing GroupCell Death and Disease2041-48892025-03-0116111510.1038/s41419-025-07485-4Senataxin prevents replicative stress induced by the Myc oncogeneSilvia Sberna0Marco Filipuzzi1Nicola Bianchi2Ottavio Croci3Federica Fardella4Chiara Soriani5Sara Rohban6Sara Carnevali7Alessandra Alberta Albertini8Nicola Crosetto9Simona Rodighiero10Arianna Chiesa11Laura Curti12Stefano Campaner13Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Imaging Unit, Department of Experimental Oncology, IEO, European Institute of Oncology IRCCSCenter for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Human TechnopoleHuman TechnopoleImaging Unit, Department of Experimental Oncology, IEO, European Institute of Oncology IRCCSCenter for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Center for Genomic Science of IIT, CGS@SEMM (Istituto Italiano di Tecnologia at European School of Molecular Medicine), Fondazione Istituto Italiano di Tecnologia (IIT)Abstract Replicative stress (RS) is emerging as a promising therapeutic target in oncology, yet full exploitation of its potential requires a detailed understanding of the mechanisms and genes involved. Here, we investigated the RNA helicase Senataxin (SETX), an enzyme that resolves RNA-DNA hybrids and R-loops, to address its role in preventing RS by oncogenic Myc. Upon Myc activation, silencing of SETX led to selective engagement of the DNA damage response (DDR) and robust cytotoxicity. Pharmacological dissection of the upstream kinases regulating the DDR uncovered a protective role of the ATR pathway, that once inhibited, boosted SETX driven-DDR. While SETX loss did not lead to a genome-wide increase of R-loops, mechanistic analyses revealed enhanced R-loops localized at DDR-foci and newly replicated genomic loci, compatible with a selective role of SETX in resolving RNA-DNA hybrids to alleviate Myc-induced RS. Genome-wide mapping of DNA double-strand breaks confirmed that SETX silencing exacerbated DNA damage at transcription-replication conflict (TRC) regions at early replicated sites. We propose that SETX prevents Myc-induced TRCs by resolving transcription-associated R-loops that encounter the replisome. The identification of SETX as a genetic liability of oncogenic Myc opens up new therapeutic options against aggressive Myc-driven tumors.https://doi.org/10.1038/s41419-025-07485-4 |
| spellingShingle | Silvia Sberna Marco Filipuzzi Nicola Bianchi Ottavio Croci Federica Fardella Chiara Soriani Sara Rohban Sara Carnevali Alessandra Alberta Albertini Nicola Crosetto Simona Rodighiero Arianna Chiesa Laura Curti Stefano Campaner Senataxin prevents replicative stress induced by the Myc oncogene Cell Death and Disease |
| title | Senataxin prevents replicative stress induced by the Myc oncogene |
| title_full | Senataxin prevents replicative stress induced by the Myc oncogene |
| title_fullStr | Senataxin prevents replicative stress induced by the Myc oncogene |
| title_full_unstemmed | Senataxin prevents replicative stress induced by the Myc oncogene |
| title_short | Senataxin prevents replicative stress induced by the Myc oncogene |
| title_sort | senataxin prevents replicative stress induced by the myc oncogene |
| url | https://doi.org/10.1038/s41419-025-07485-4 |
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