RGG-motif proteins regulate mRNA translation upon genotoxic stress

Abstract

AbstractRGG motif-containing proteins are the second largest group of RNA-binding proteins. These proteins have been implicated in several cellular processes. Here we identify a new role of yeast RGG-motif proteins Sbp1, Scd6, and its human ortholog LSM14A, in genotoxic stress response. Scd6 and Sbp1 colocalize to cytoplasmic puncta upon hydroxyurea (HU) treatment, and Scd6 is required for the efficient localization of Sbp1. These puncta are reversible and require RNA for their assembly. The RGG-motif is important for the localization of both proteins to puncta. Strikingly, the absence of Scd6 increases HU tolerance under normal conditions but sensitizes the cells to HU upon overexpression of Srs2, which is known to dampen the response to DNA damage. LSM14A also localizes to puncta in response to genotoxic stress such as HU and cisplatin. This localization also depends on the two RGG motifs of LSM14A. While proximity ligation assay reveals that LSM14A is associated with the translation initiation factor eIF4G, polysome profiling experiments followed by RNA sequencing identify numerous transcripts that are regulated by LSM14A at the translational level under normal conditions and in response to HU. Our work identifies RGG motif-containing proteins as key players in orchestrating genotoxic stress response by determining the translation status of a subset of mRNAs.