Secretariat, Alumni Association, IDAC
Date Monday, 25 September 2023, 17:00~18:30
Room 7th Floor, Seminar Room 1, IDAC Center for Basic Aging Research
Title Identification of Druggable and Redox Vulnerabilities in Cancer
Speaker Liron Bar-Peled, PhD
Affiliation MGH Cancer Center, Harvard Medical School Department of Medicine
Organizer Hozumi Motohashi (Dept. Gene Expression Regulation・ext 8550)
Abstract Multiple 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 H2O2 sensor 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 H2O2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.