Faculty, Staff and Student Publications
Publication Date
6-18-2024
Journal
eLife
DOI
10.7554/eLife.91611
PMID
38896450
PMCID
PMC11186636
PubMedCentral® Posted Date
June 2024
PubMedCentral® Full Text Version
Post-print
Abstract
The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.
Keywords
Protein Phosphatase 2C, Humans, Superoxide Dismutase-1, Cell Line, Tumor, Leukemia, CRISPR-Cas Systems, Oxidative Stress, Reactive Oxygen Species, Synthetic Lethal Mutations, Mutation
Published Open-Access
yes
Recommended Citation
Zhang, Linda; Hsu, Joanne I; Braekeleer, Etienne D; et al., "SOD1 Is a Synthetic-Lethal Target in PPM1D-Mutant Leukemia Cells" (2024). Faculty, Staff and Student Publications. 2160.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/2160
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