ArticlePLoS genetics2013
An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-spectrum target for anticancer therapeutic development.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 89 citations in OpenAlex.
- A dual mode one-pot assay detecting FEN1 activity through magnetic separation-based cascade exponential amplification strategy.Mikrochimica acta · 2026Article
- Synthetic lethality in cancer drug discovery: challenges and opportunities.Nature reviews. Drug discovery · 2026Review
- A global genetic interaction map of a human cell reveals conserved principles of genetic networks.bioRxiv : the preprint server for biology · 2025Article
- PROTACs: Current and Future Potential as a Precision Medicine Strategy to Combat Cancer.Molecular cancer therapeutics · 2024Review
- Base Excision Repair: Mechanisms and Impact in Biology, Disease, and Medicine.International journal of molecular sciences · 2023Review
- FEN1 inhibitor synergizes with low-dose camptothecin to induce increased cell killing via the mitochondria mediated apoptotic pathway.Gene therapy · 2022Article
- Theranostic Interpolation of Genomic Instability in Breast Cancer.International journal of molecular sciences · 2022Review
- Fragment- and structure-based drug discovery for developing therapeutic agents targeting the DNA Damage Response.Progress in biophysics and molecular biology · 2021Article
- The prognostic significance of Flap Endonuclease 1 (FEN1) in breast ductal carcinoma in situ.Breast cancer research and treatment · 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
- Review
- Implementing fluorescence enhancement, quenching, and FRET for investigating flap endonuclease 1 enzymatic reaction at the single-molecule level.Computational and structural biotechnology journal · 2021Review
- Exploring Candidate Human Synthetic Lethal Interactions Through siRNA and Quantitative Imaging-Based Approaches.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Employing Cross-Species Approaches to Construct Humanized Genetic Interaction Networks.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Base excision repair and its implications to cancer therapy.Essays in biochemistry · 2020Review
- Cross-Species Complementation of Nonessential Yeast Genes Establishes Platforms for Testing Inhibitors of Human Proteins.Genetics · 2020Article
- Human artificial chromosome (HAC) for measuring chromosome instability (CIN) and identification of genes required for proper chromosome transmission.Experimental cell research · 2020Review
- Mdivi-1 and mitochondrial fission: recent insights from fungal pathogens.Current genetics · 2019Review
- The natural anticancer agent cantharidin alters GPI-anchored protein sorting by targeting Cdc1-mediated remodeling in endoplasmic reticulum.The Journal of biological chemistry · 2019Article
- Genetic interaction networks mediate individual statin drug response inNPJ systems biology and applications · 2019Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
Harnessing genetic differences between cancerous and noncancerous cells offers a strategy for the development of new therapies. Extrapolating from yeast genetic interaction data, we used cultured human cells and siRNA to construct and evaluate a synthetic lethal interaction network comprised of chromosome instability (CIN) genes that are frequently mutated in colorectal cancer. A small number of genes in this network were found to have synthetic lethal interactions with a large number of cancer CIN genes; these genes are thus attractive targets for anticancer therapeutic development. The protein product of one highly connected gene, the flap endonuclease FEN1, was used as a target for small-molecule inhibitor screening using a newly developed fluorescence-based assay for enzyme activity. Thirteen initial hits identified through in vitro biochemical screening were tested in cells, and it was found that two compounds could selectively inhibit the proliferation of cultured cancer cells carrying inactivating mutations in CDC4, a gene frequently mutated in a variety of cancers. Inhibition of flap endonuclease activity was also found to recapitulate a genetic interaction between FEN1 and MRE11A, another gene frequently mutated in colorectal cancers, and to lead to increased endogenous DNA damage. These chemical-genetic interactions in mammalian cells validate evolutionarily conserved synthetic lethal interactions and demonstrate that a cross-species candidate gene approach is successful in identifying small-molecule inhibitors that prove effective in a cell-based cancer model.
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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.