SRSF2 overexpression induces transcription-/replication-dependent DNA double-strand breaks and interferes with DNA repair pathways to promote lung tumor progression
SRSF2 (serine/arginine-rich splicing factor 2) is a critical regulator of pre-messenger RNA splicing, which also plays noncanonical functions in transcription initiation and elongation. Although elevated levels of SRSF2 are associated with advanced stages of lung adenocarcinoma (LUAD), the mechanisms connecting SRSF2 to lung tumor progression remain unknown. We show that SRSF2 overexpression increases global transcription and replicative stress in LUAD cells, which correlates with the production of DNA damage, notably double-strand breaks (DSBs), likely resulting from conflicts between transcription and replication. Moreover, SRSF2 regulates DNA repair pathways by promoting homologous recombination and inhibiting nonhomologous end joining. Mechanistically, SRSF2 interacts with and enhances MRE11 (meiotic recombination 11) recruitment to chromatin, while downregulating 53BP1 messenger RNA and protein levels. Both events are likely contributing to SRSF2-mediated DNA repair process rerouting. Lastly, we show that SRSF2 and MRE11 expression is commonly elevated in LUAD and predicts poor outcome of patients. Altogether, our results identify a mechanism by which SRSF2 overexpression promotes lung cancer progression through a fine control of both DSB production and repair. Finally, we show that SRSF2 knockdown impairs late repair of ionizing radiation-induced DSBs, suggesting a more global function of SRSF2 in DSB repair by homologous recombination.
Authors
- Olivier Sordet (ORCID: https://orcid.org/0000-0001-6027-4925)
- Carmen Garrido (ORCID: https://orcid.org/0000-0003-1368-1493)
- Sylvie Gazzéri (ORCID: https://orcid.org/0000-0001-5817-1839)
- Ester M. Hammond (ORCID: https://orcid.org/0000-0002-2335-3146)
- Shaliny Ramachandran
- Élisabeth Brambilla (ORCID: https://orcid.org/0000-0001-7559-2141)
- Aurélie Genoux (ORCID: https://orcid.org/0000-0002-1397-191X)
- Pierre Caron (ORCID: https://orcid.org/0000-0003-2353-5684)
- Marie Leverve
- Pablo Huertas (ORCID: https://orcid.org/0000-0002-1756-4449)
- Néstor García‐Rodríguez (ORCID: https://orcid.org/0000-0002-4049-1604)
- Fabien Dalonneau
- Guillaume Marcion (ORCID: https://orcid.org/0000-0002-3634-6316)
- Béatrice Eymin (ORCID: https://orcid.org/0000-0002-7311-3810)
- Nina Lepeltier
- Nicolas Lemaître (ORCID: https://orcid.org/0000-0003-1768-9679)
- Tao Jia (ORCID: https://orcid.org/0000-0002-8358-6005)
- Agnese Cristini (ORCID: https://orcid.org/0000-0003-0235-8770)
- Amélie Pucciarelli
- Manal Khalifé
- Amani Shreim
- Lara Fernandez Martinez
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Bourgogne (FR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- University of Oxford (GB)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- CRUK/MRC Oxford Institute for Radiation Oncology (GB)
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES)
- Universidad de Sevilla (ES)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- NAR Cancer
- Published
- 2025-03-13
- DOI
- https://doi.org/10.1093/narcan/zcaf011
- Citations
- 4
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Université Grenoble Alpes
- Infrastructures en Biologie Santé et Agronomie
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation pour la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Fondation de France
- Centre National de la Recherche Scientifique
- Ministerio de Ciencia e Innovación
- Institut National Du Cancer
- Région Auvergne-Rhône-Alpes
- Junta de Andalucía
- Groupement des Entreprises Françaises dans la lutte contre le Cancer
- Agencia Estatal de Investigación