Induction of Stress Granule Assembly is Essential for the Orchestration of DNA Damage Response

Nicole Verkaik,Stephan Persengiev

doi:10.1038/npre.2008.1591.1

Abstract

AbstractDNA damage provokes several responses including DNA repair, cell cycle regulation and apoptosis that collectively represent the DNA damage response (DDR). Here, we demonstrate that the DDR incorporates the activation of stress granule (SG) formation pathway as a mechanism to process destabilized RNAs. UV irradiation induced the assembly of SGs during the G2 phase and newly formed SGs appeared exclusively in the early G1 phase. SG assembly pathway was activated within the first hours after DNA damage, suggesting that the processing of destabilized RNAs is activated at an early stage. The induction of SGs and RNAi effector protein Argonaute 2 recruitment after UV exposure was independent of ATM and ATR signaling cascades. Apoptosis occurred only in SG-negative cells indicating that SGs promote cell survival after genotoxic stress. Analysis of several DNA damage/repair deficient MEFs revealed that the SG accumulation remained unaltered after UV exposure. Our results show that SGs are an essential component of DDR that is activated in parallel to the DNA damage kinase response networks.

Highlights

Various endogenous and exogenous agents such as metabolic byproducts and natural UV irradiation continuously damage the cellular DNA
We explored the possible involvement of RNA silencing in the regulation of mRNA processing after DNA damage
MiRNAs have been found to relocalize to dynamically assembled perinuclear structures in response to stress stimuli identified as stress granules (SGs) (Anderson and Kedersha 2002)

Summary

Introduction

We demonstrate that miRNA-mediated gene silencing is an active component of the DDR, which acts as an intermediate response between the fast changes in protein modifications and the relatively slow transcriptional reprogramming after DNA damage. We interrogated whether UV-induced DNA damage leads to activation of RNAi pathways and SG formation in HeLa cells and primary human fibroblasts.

Results

Conclusion