ArticlePloS one2017
Small molecule inhibitors uncover synthetic genetic interactions of human flap endonuclease 1 (FEN1) with DNA damage response genes.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 44 citations in OpenAlex.
- Mechanistic insights into the monotherapy and combination potential of FEN1 inhibition in cancer therapy.Nucleic acids research · 2025Article
- Article
- Structure-specific nucleases in genome dynamics and strategies for targeting cancers.Journal of molecular cell biology · 2024Review
- PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair.The EMBO journal · 2024Article
- Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing.Nature communications · 2023Article
- Metformin sensitises osteosarcoma to chemotherapy <em>via</em> the IGF-1R/miR-610/FEN1 pathway.European journal of histochemistry : EJH · 2023Article
- Exploiting replication gaps for cancer therapy.Molecular cell · 2022Review
- Targeting DNA damage response components induces enhanced STING-dependent type-I IFN response in ATM deficient cancer cells and drives dendritic cell activation.Oncoimmunology · 2022Article
- Persistent DNA damage signaling and DNA polymerase theta promote broken chromosome segregation.The Journal of cell biology · 2021Article
- Revisiting the BRCA-pathway through the lens of replication gap suppression: "Gaps determine therapy response in BRCA mutant cancer".DNA repair · 2021Review
- Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency.Molecular cell · 2021Article
- Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response.Progress in biophysics and molecular biology · 2021Article
- FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers.Cancers · 2021Article
- Modeling DNA trapping of anticancer therapeutic targets using missense mutations identifies dominant synthetic lethal interactions.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- FEN1 is a prognostic biomarker for ER+ breast cancer and associated with tamoxifen resistance through the ERα/cyclin D1/Rb axis.Annals of translational medicine · 2021Article
- Implementing fluorescence enhancement, quenching, and FRET for investigating flap endonuclease 1 enzymatic reaction at the single-molecule level.Computational and structural biotechnology journal · 2021Review
- Draining the FEN1s for cancer therapy.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- WRNIP1 Is Recruited to DNA Interstrand Crosslinks and Promotes Repair.Cell reports · 2020Article
- Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Flap endonuclease 1 (FEN1) is a structure selective endonuclease required for proficient DNA replication and the repair of DNA damage. Cellularly active inhibitors of this enzyme have previously been shown to induce a DNA damage response and, ultimately, cell death. High-throughput screens of human cancer cell-lines identify colorectal and gastric cell-lines with microsatellite instability (MSI) as enriched for cellular sensitivity to N-hydroxyurea series inhibitors of FEN1, but not the PARP inhibitor olaparib or other inhibitors of the DNA damage response. This sensitivity is due to a synthetic lethal interaction between FEN1 and MRE11A, which is often mutated in MSI cancers through instabilities at a poly(T) microsatellite repeat. Disruption of ATM is similarly synthetic lethal with FEN1 inhibition, suggesting that disruption of FEN1 function leads to the accumulation of DNA double-strand breaks. These are likely a result of the accumulation of aberrant replication forks, that accumulate as a consequence of a failure in Okazaki fragment maturation, as inhibition of FEN1 is toxic in cells disrupted for the Fanconi anemia pathway and post-replication repair. Furthermore, RAD51 foci accumulate as a consequence of FEN1 inhibition and the toxicity of FEN1 inhibitors increases in cells disrupted for the homologous recombination pathway, suggesting a role for homologous recombination in the resolution of damage induced by FEN1 inhibition. Finally, FEN1 appears to be required for the repair of damage induced by olaparib and cisplatin within the Fanconi anemia pathway, and may play a role in the repair of damage associated with its own disruption.
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