Author:
Zhang Junbing,Simpson Claire M.,Berner Jacqueline,Chong Harrison B.,Fang Jiafeng,Sahin Zehra Ordulu,Weiss-Sadan Tom,Possemato Anthony P.,Harry Stefan,Takahashi Mariko,Yang Tzu-yi,Richter Marianne,Patel Himani,Smith Abby E.,Carlin Alexander D.,Hubertus de Groot Adriaan F.,Wolf Konstantin,Shi Lei,Wei Ting-Yu,Dürr Benedikt R.,Chen Nicholas J.,Vornbäumen Tristan,Wichmann Nina O.,Pooladanda Venkatesh,Matoba Yuske,Kumar Shaan,Kim Eugene,Bouberhan Sara,Olivia Esther,Rueda Bo,Bardeesy Nabeel,Liau Brian,Lawrence Michael,Stokes Matt P.,Beausoleil Sean A.,Bar-Peled Liron
Abstract
AbstractMultiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it’s unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H2O2sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H2O2accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.
Publisher
Cold Spring Harbor Laboratory