DNA damage promotes ER stress resistance through elevation of unsaturated phosphatidylcholine in Caenorhabditis elegans

Abstract

DNA damage triggers the cellular adaptive response to arrest proliferation and repair DNA damage; when damage is too severe to be repaired, apoptosis is initiated to prevent the spread of genomic insults. However, how cells endure DNA damage to maintain cell function remains largely unexplored. By using Caenorhabditis elegans as a model, we report that DNA damage elicits cell maintenance programs, including the unfolded protein response of the endoplasmic reticulum (UPR^ER). Mechanistically, sublethal DNA damage unexpectedly suppresses apoptotic genes in C. elegans, which in turn increases the activity of the inositol-requiring enzyme 1/X-box binding protein 1 (IRE-1/XBP-1) branch of the UPR^ER by elevating unsaturated phosphatidylcholine. In addition, UPR^ER activation requires silencing of the lipid regulator skinhead-1 (SKN-1). DNA damage suppresses SKN-1 activity to increase unsaturated phosphatidylcholine and activate UPR^ER. These findings reveal the UPR^ER activation as an organismal adaptive response that is important to maintain cell function during DNA damage.

Keywords: C. elegans; DNA damage response; ER stress response; SKN-1; apoptotic genes; fatty acid; phosphatidylcholine.