Related Experiment Video
Updated: Aug 6, 2025
Author Spotlight: Detection of Mitophagy in Caenorhabditis elegans and Mammalian Cells Using Organelle-Specific Dyes
Published on: May 19, 2023
Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway
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 H 2 O 2 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 H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H 2 O 2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.
Insights
Chemotherapies increase reactive oxygen species (ROS), but how cells sense and respond remains unclear. This study identifies a nucleus-to-mitochondria pathway involving CHK1 and SSBP1 that resolves ROS and mediates resistance to platinum-based chemotherapy in ovarian cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Chemotherapies induce cell death partly via reactive oxygen species (ROS), but the precise mechanisms of ROS function and sensing are poorly understood.
- Identifying ROS-modified proteins and their roles in chemotherapy sensitivity or resistance is crucial for developing effective cancer treatments.
Approach:
- Utilized an integrated proteogenomic approach to analyze 11 chemotherapies.
- Identified both unique and shared protein targets, including ribosomal components, suggesting a role in translation regulation.
- Focused on CHK1 as a key nuclear hydrogen peroxide (H2O2) sensor.
Key Points:
- CHK1 acts as a nuclear H2O2 sensor, initiating an anti-ROS cellular program.
- CHK1 phosphorylates SSBP1, inhibiting its mitochondrial import and reducing nuclear H2O2 levels.
- This nucleus-to-mitochondria signaling pathway is essential for resolving nuclear ROS accumulation.
Conclusions:
- Discovered a druggable pathway for sensing and resolving nuclear ROS.
- This pathway is critical for mediating resistance to platinum-based chemotherapies in ovarian cancers.
- Findings offer potential therapeutic targets for overcoming chemotherapy resistance.
Related Concept Videos
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...
01:19Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...