ArticleNucleic acids research2019
Synthetic lethality between BRCA1 deficiency and poly(ADP-ribose) polymerase inhibition is modulated by processing of endogenous oxidative DNA damage.
Article in Nucleic acids research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 39 citations in OpenAlex.
- PAK1 inhibition synergistically enhances the anti-tumor efficacy of PARP inhibitors in ovarian cancers.Genes & diseases · 2026Article
- Resveratrol potentiates chemotherapeutic efficacy of olaparib in MCF7 human breast cancer cells by inducing apoptosis.Irish journal of medical science · 2026Article
- The role of HECT-type E3 ubiquitin ligases in DNA damage response and repair.Cell death discovery · 2025Review
- Neomorphic leukemia-derived mutations in the TET2 enzyme induce genome instability via a substrate shift from 5-methylcytosine to thymine.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Unprocessed genomic uracil as a source of DNA replication stress in cancer cells.Molecular cell · 2024Article
- Article
- The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells.Cancers · 2023Article
- Clinical application of PARP inhibitors in ovarian cancer: from molecular mechanisms to the current status.Journal of ovarian research · 2023Review
- A prognostic model based on prognosis-related ferroptosis genes for patients with acute myeloid leukemia.Frontiers in molecular biosciences · 2023Article
- OGG1 competitive inhibitors show important off-target effects by directly inhibiting efflux pumps and disturbing mitotic progression.Frontiers in cell and developmental biology · 2023Article
- Review
- Targeting the DNA Damage Response and DNA Repair Pathways to Enhance Radiosensitivity in Colorectal Cancer.Cancers · 2022Review
- Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies.Journal of hematology & oncology · 2022Review
- OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells.Frontiers in oncology · 2022Article
- Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines.International journal of molecular sciences · 2021Article
- Research progress on the association between environmental pollutants and the resistance mechanism of PARP inhibitors in ovarian cancer.Environmental science and pollution research international · 2021Review
- Small molecule inhibitor of OGG1 blocks oxidative DNA damage repair at telomeres and potentiates methotrexate anticancer effects.Scientific reports · 2021Article
- Relationship betweenMolecular and clinical oncology · 2021Article
- Synthetic Lethality through the Lens of Medicinal Chemistry.Journal of medicinal chemistry · 2020Review
- Down-regulation of PADI2 prevents proliferation and epithelial-mesenchymal transition in ovarian cancer through inhibiting JAK2/STAT3 pathway in vitro and in vivo, alone or in combination with Olaparib.Journal of translational medicine · 2020Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Poly(ADP-ribose) polymerases (PARPs) facilitate the repair of DNA single-strand breaks (SSBs). When PARPs are inhibited, unrepaired SSBs colliding with replication forks give rise to cytotoxic double-strand breaks. These are normally rescued by homologous recombination (HR), but, in cells with suboptimal HR, PARP inhibition leads to genomic instability and cell death, a phenomenon currently exploited in the therapy of ovarian cancers in BRCA1/2 mutation carriers. In spite of their promise, resistance to PARP inhibitors (PARPis) has already emerged. In order to identify the possible underlying causes of the resistance, we set out to identify the endogenous source of DNA damage that activates PARPs. We argued that if the toxicity of PARPis is indeed caused by unrepaired SSBs, these breaks must arise spontaneously, because PARPis are used as single agents. We now show that a significant contributor to PARPi toxicity is oxygen metabolism. While BRCA1-depleted or -mutated cells were hypersensitive to the clinically approved PARPi olaparib, its toxicity was significantly attenuated by depletion of OGG1 or MYH DNA glycosylases, as well as by treatment with reactive oxygen species scavengers, growth under hypoxic conditions or chemical OGG1 inhibition. Thus, clinical resistance to PARPi therapy may emerge simply through reduced efficiency of oxidative damage repair.
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