Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway

Zhang, J.; Simpson, C. M.; Berner, J.; Chong, H. B.; Fang, J.; Sahin, Z. O.; Weiss-Sadan, T.; Possemato, A. P.; Harry, S.; Takahashi, M.; Yang, T.-y.; Richter, M.; Patel, H.; Smith, A. E.; Carlin, A. D.; Hubertus de Groot, A. F.; Wolf, K.; Shi, L.; Wei, T.-Y.; Durr, B. R.; Chen, N. J.; Vornbaumen, T.; Wichmann, N. O.; Pooladanda, V.; Matoba, Y.; Kumar, S.; Kim, E.; Bouberhan, S.; Olivia, E.; Rueda, B.; Bardeesy, N.; Liau, B.; Lawrence, M.; Stokes, M. P.; Beausoleil, S. A.; Bar-Peled, L.

doi:10.1101/2023.03.11.532189

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bioRxiv · 10.1101/2023.03.11.532189

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway

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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, its 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.

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Zhang, J., Simpson, C. M., Berner, J., Chong, H. B., Fang, J., Sahin, Z. O., Weiss-Sadan, T., Possemato, A. P., Harry, S., Takahashi, M., Yang, T.-y., Richter, M., Patel, H., Smith, A. E., Carlin, A. D., Hubertus de Groot, A. F., Wolf, K., Shi, L., Wei, T.-Y., Durr, B. R., Chen, N. J., Vornbaumen, T., Wichmann, N. O., Pooladanda, V., Matoba, Y., Kumar, S., Kim, E., Bouberhan, S., Olivia, E., Rueda, B., Bardeesy, N., Liau, B., Lawrence, M., Stokes, M. P., Beausoleil, S. A., Bar-Peled, L.. 2023-03-11. Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway. https://doi.org/10.1101/2023.03.11.532189

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