RGG motif-containing Scd6/LSM14A proteins regulate the translation of specific mRNAs in response to hydroxyurea-induced genotoxic stress

Abstract

Genotoxic stress response (GSR) mediated by mRNA translation and decay regulation remains poorly explored. Here, we identify a unique role of yeast RGG-motif protein Scd6 and its human ortholog LSM14A in mRNA translation control upon hydroxyurea (HU)-mediated GSR. Scd6/LSM14A, but not all tested RGG-containing proteins, localize to HU-induced cytoplasmic puncta in an RGG-dependent manner. The absence of Scd6 increases HU tolerance but sensitizes the cells to HU upon overexpression of SRS2, a known dampener of the DNA- damage response. Scd6 binds SRS2 mRNA to repress its translation in cytoplasmic granules upon HU stress. Scd6-SRS2 interaction is modulated by arginine methylation (AM) and the LSm-domain, which acts as a cis-regulator of Scd6 AM. Polysome-profiling experiments indicate that LSM14A regulates the translation of NHEJ factor mRNAs such as LIG4 (DNL4 homolog) and RTEL1 (SRS2 functional homolog), and the NHEJ activity in response to HU. Overall, this report unveils the role of AM and Scd6/LSM14A in the GSR by determining the translation status of specific mRNAs.