Genotoxic 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 (Non-homologous end-joining) proteins such as RTEL1 (SRS2 functional homolog) and LIG4. NHEJ activity in yeast and mammalian cells is regulated by Scd6 and LSM14A, respectively. Overall, this report unveils the role of RNA binding proteins in regulating the translation of specific mRNAs coding for DNA damage response proteins upon genotoxic stress.