biostudies-literatureMohanan GEquipexAgence Nationale de la RechercheWellcome Trust DBT India Alliance (India Alliance)Equipe labellisée Ligue Nationale Contre le CancerFrance Génomique ConsortiumDBT/Wellcome Trust India AllianceDepartment of Science and Technology, Ministry of Science and Technology, IndiaIndo-French Centre for the Promotion of Advanced Research (IFCPAR)SiRIC GrantInstitut Curie, Gustave Roussy, INSERM, CNRSITMO-Cancer AviesanIndo-French Centre for the Promotion of Advanced ResearchMinistry of Education, IndiaDepartment of Biotechnology, Ministry of Science and Technology, India (DBT)Wellcome TrustDepartment of Biotechnology, Ministry of Science and Technology, India2715-2739https://www.ebi.ac.uk/biostudies/studies/S-EPMC12116771biostudies-literatureUnknown26(10)The role of mRNA translation and decay in the genotoxic stress response remains poorly explored. Here, we identify the role of yeast RGG motif-containing RNA binding protein Scd6 and its human ortholog LSM14A in genotoxic stress response. Scd6 localizes to cytoplasmic puncta upon cell treatment with various genotoxic agents. Scd6 genetically interacts with SRS2, a DNA helicase with an anti-recombination role in DNA damage repair under HU stress. Scd6 directly interacts with the SRS2 mRNA to repress its translation in cytoplasmic granules upon HU stress in an eIF4G1-independent manner. Scd6-SRS2 interaction is modulated by arginine methylation and the LSm-domain of Scd6, which acts as a cis-regulator of Scd6 arginine methylation. LSM14A regulates the translation of mRNAs encoding key NHEJ (EMBO reportsGenotoxic stress triggers Scd6-dependent regulation of translation to modulate the DNA damage response.PMC12116771ANR-10-EQPX-03INCa-DGOS-4657003-H/7003-2IA/I/12/2/500625INCa-DGOS- Inserm_12554BT/PR51975/BMS/85/23/2024ANR-10-INBS-09-08Vagner SRajyaguru PIMohanan GLamba SRoy RMalka-Mahieu HFabbri LKalia SBiswas AM Labbe CMartineau SfalseGenotoxic stress triggers Scd6-dependent regulation of translation to modulate the DNA damage response.The role of mRNA translation and decay in the genotoxic stress response remains poorly explored. Here, we identify the role of yeast RGG motif-containing RNA binding protein Scd6 and its human ortholog LSM14A in genotoxic stress response. Scd6 localizes to cytoplasmic puncta upon cell treatment with various genotoxic agents. Scd6 genetically interacts with SRS2, a DNA helicase with an anti-recombination role in DNA damage repair under HU stress. Scd6 directly interacts with the SRS2 mRNA to repress its translation in cytoplasmic granules upon HU stress in an eIF4G1-independent manner. Scd6-SRS2 interaction is modulated by arginine methylation and the LSm-domain of Scd6, which acts as a cis-regulator of Scd6 arginine methylation. LSM14A regulates the translation of mRNAs encoding key NHEJ (2025-01-01T00:00:00Z2025 May2026-06-03T07:48:20.42Z2026-04-26T03:10:16.491ZS-EPMC121167714027510610.1038/s44319-025-00443-3