ArticleThe EMBO journal2024
PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair.
Article in The EMBO journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 21 citations in OpenAlex.
- Epigenetic Plasticity in Triple-Negative Breast Cancer: Mechanisms of Therapy Resistance, Biomarkers, and Therapeutic Vulnerabilities.Biomedicines · 2026Review
- FET proteins and PARylation-dependent condensates promote replication fork reversal and genome stability.Nature communications · 2026Article
- The Expanding Landscape of ADP-Ribosylation: Protein, DNA, RNA, and Mitochondrial Regulation.Chemical research in toxicology · 2026Review
- Clinical application of PARP inhibitors and emerging strategies to overcome resistance: a pan-cancer perspective.Biomarker research · 2026Review
- MDC1 counteracts replication fork reversal and mediates chemosensitivity in BRCA1/2-deficient tumors.Oncogene · 2026Article
- Rotenone Inhibited Osteosarcoma Cell Growth Through USP47-Induced Decreases in FEN1 Stability and DNA Integrity.Drug design, development and therapy · 2026Article
- PARG inhibition suppresses breast cancer progression and potentiates immunoresponse through MTDH degradation mediated by E3 ligase ITCH-dependent ubiquitination.NPJ breast cancer · 2025Article
- Replication-associated base excision repair/single-strand break repair regulates PARG inhibitor response via the PRMT1/PRMT5/ATR axis.NAR cancer · 2025Article
- Targeting DNA Damage Repair Pathways Beyond PARP Inhibition.Targeted oncology · 2025Review
- BRCA2 deficiency and replication stress drive APOBEC3-Mediated genomic instability.Nature communications · 2025Article
- Prospects for PARG inhibitors in cancer therapy.Journal of molecular cell biology · 2025Review
- Targeting FEN1/EXO1 to enhance efficacy of PARP inhibition in triple-negative breast cancer.Translational oncology · 2025Article
- Identification of EXO1 as a potential biomarker associated with prognosis and tumor immune microenvironment for specific human cancers.Mammalian genome : official journal of the International Mammalian Genome Society · 2025Article
- Suppression of ADP-ribosylation reversal triggers cell vulnerability to alkylating agents.Neoplasia (New York, N.Y.) · 2025Article
- PARG inhibitor sensitivity correlates with accumulation of single-stranded DNA gaps in preclinical models of ovarian cancer.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Intrinsic PARG inhibitor sensitivity is mimicked byNAR cancer · 2024Article
- The bioinformatics analysis and experimental validation of the carcinogenic role of EXO1 in lung adenocarcinoma.Frontiers in oncology · 2024Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 3 countries.
Funding
Abstract
Targeting poly(ADP-ribose) glycohydrolase (PARG) is currently explored as a therapeutic approach to treat various cancer types, but we have a poor understanding of the specific genetic vulnerabilities that would make cancer cells susceptible to such a tailored therapy. Moreover, the identification of such vulnerabilities is of interest for targeting BRCA2;p53-deficient tumors that have acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) through loss of PARG expression. Here, by performing whole-genome CRISPR/Cas9 drop-out screens, we identify various genes involved in DNA repair to be essential for the survival of PARG;BRCA2;p53-deficient cells. In particular, our findings reveal EXO1 and FEN1 as major synthetic lethal interactors of PARG loss. We provide evidence for compromised replication fork progression, DNA single-strand break repair, and Okazaki fragment processing in PARG;BRCA2;p53-deficient cells, alterations that exacerbate the effects of EXO1/FEN1 inhibition and become lethal in this context. Since this sensitivity is dependent on BRCA2 defects, we propose to target EXO1/FEN1 in PARPi-resistant tumors that have lost PARG activity. Moreover, EXO1/FEN1 targeting may be a useful strategy for enhancing the effect of PARG inhibitors in homologous recombination-deficient tumors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.