Redox regulation and DNA repair coordination are essential for genomic stability. Peroxiredoxin 1 (PRDX1) is a thiol-dependent peroxidase and a chaperone that protects proteins from excessive oxidation. ATM kinase (Ataxia-Telangiectasia Mutated) and the MRN (MRE11-RAD50-NBS1) complex are DNA damage signaling and repair proteins. We previously showed that cells lacking PRDX1 are sensitive to arsenite, a toxic metal that induces DNA single- and double-strand breaks (DSBs). Herein, we showed that PRDX1 interacts with ATM. PRDX1-deleted cells have reduced ATM, MRE11, and RAD50 protein levels, but not NBS1. In control cells treated with arsenite, we observed γH2AX foci formation due to arsenite-induced DSBs, and not from PRDX1-deleted cells. Arsenite caused profound depletion of ATM in PRDX1-deleted cells, suggesting that PRDX1 protects and stabilizes ATM required to form γH2AX foci. Importantly, arsenite pretreatment of PRDX1-deleted cells caused hypersensitivity to chemotherapeutic agents that generate DSBs. Analysis of a clinical cohort of ovarian cancers treated with platinum chemotherapy revealed that tumours with high PRDX1/high ATM or high PRDX1/high MRE11 expression manifested aggressive phenotypes and poor patient survival. The data suggest that PRDX1 can predict responses to chemotherapy, and targeting PRDX1 could be a viable strategy to improve the efficacy of platinum chemotherapy.
PRDX1 protects ATM from arsenite-induced proteotoxicity and maintains its stability during DNA damage signaling.
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作者:Ali Reem, Algethami Mashael, Sheha Amera, Alqahtani Shatha, Altayyar Ahmad, Lashen Ayat, Rakha Emad, Sulaiman Abdallah Alhaj, Madhusudan Srinivasan, Ramotar Dindial
期刊: | Oncotarget | 影响因子: | 0.000 |
时间: | 2025 | 起止号: | 2025 May 19; 16:362-378 |
doi: | 10.18632/oncotarget.28720 |
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