AI Article Synopsis
- The DNA damage response is crucial for keeping our genetic material stable and its disruption is often linked to cancer development.
- PPM1D acts as a key negative regulator of this response, and mutations in this gene have been found in various cancers, making it a potential target for new treatments.
- Using CRISPR/Cas9 screening, researchers identified SOD1 as a promising target for cells with PPM1D mutations, showing that these cells have higher levels of reactive oxygen species and struggle with oxidative stress, indicating a new cancer therapy approach.
Article 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 are found across several human cancers making it a relevant pharmacologic target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of 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 -mutant cells. Altogether, our results demonstrate the protective role of SOD1 against oxidative stress in -mutant leukemia cells and highlight a new potential therapeutic strategy against -mutant cancers.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491179 | PMC |
| http://dx.doi.org/10.1101/2023.08.31.555634 | DOI Listing |
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