Fiche publication
Date publication
juin 2025
Journal
NAR cancer
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GARRIDO Carmen
Tous les auteurs :
Khalife M, Jia T, Caron P, Shreim A, Genoux A, Cristini A, Pucciarelli A, Leverve M, Lepeltier N, García-Rodríguez N, Dalonneau F, Ramachandran S, Fernandez Martinez L, Marcion G, Lemaitre N, Brambilla E, Garrido C, Hammond EM, Huertas P, Gazzeri S, Sordet O, Eymin B
Lien Pubmed
Résumé
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.
Mots clés
Serine-Arginine Splicing Factors, genetics, Humans, Lung Neoplasms, genetics, DNA Breaks, Double-Stranded, DNA Repair, genetics, Disease Progression, MRE11 Homologue Protein, metabolism, Adenocarcinoma of Lung, genetics, DNA Replication, Cell Line, Tumor, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Homologous Recombination
Référence
NAR Cancer. 2025 06;7(2):zcaf011
