Genotoxic stress triggers the activation of IRE1?-dependent RNA decay to modulate the DNA damage response.

ABSTRACT: The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1? under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1? signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1?-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1? endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1? to catalyze RIDD. The protective role of IRE1? under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.

SUBMITTER: Dufey E 

PROVIDER: S-EPMC7224204 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature