Inhibition of the ERCC1–XPF structure-specific endonuclease to overcome cancer chemoresistance
| Autor: | David W. Melton, Douglas R. Houston, Preeti Bakrania, Martin A. Wear, Barbara Saxty, Ann Marie Ritchie, Steven Shave, Tim Chapman, Katy R. Astell, Puneet Khurana, Claire Wallace, Ewan M. McNeil, Malcolm D. Walkinshaw, Hayley M. Jones |
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| Rok vydání: | 2015 |
| Předmět: |
DNA Repair
REPAIR/RECOMBINATION NUCLEASE Biochemistry Endonuclease chemistry.chemical_compound Catalytic Domain CRYSTAL-STRUCTURE Melanoma FANCQ Ovarian Neoplasms biology INTERACTION DOMAINS DNA-Binding Proteins Gene Expression Regulation Neoplastic DNA-REPAIR Female MESSENGER-RNA Interstrand Crosslink Repair medicine.drug GENE ERCC1 DNA repair CELL LUNG-CANCER In silico CISPLATIN Ovarian cancer Cell Line Tumor medicine Humans Molecular Biology Cisplatin Reproducibility of Results Cancer Sequence Analysis DNA Cell Biology Endonucleases medicine.disease Molecular biology High-Throughput Screening Assays NUCLEOTIDE EXCISION-REPAIR chemistry Drug Resistance Neoplasm DNA repair inhibitor biology.protein Cancer research ERCC1-XPF Nucleotide Excision Repair SMALL-MOLECULE INHIBITORS ERCC1 DNA Nucleotide excision repair |
| Zdroj: | McNeil, E M, Astell, K R, Ritchie, A-M, Shave, S, Houston, D R, Bakrania, P, Jones, H M, Khurana, P, Wallace, C, Chapman, T, Wear, M A, Walkinshaw, M D, Saxty, B & Melton, D W 2015, ' Inhibition of the ERCC1-XPF structure-specific endonuclease to overcome cancer chemoresistance ', DNA Repair, vol. 31, pp. 19-28 . https://doi.org/10.1016/j.dnarep.2015.04.002 |
| ISSN: | 1568-7864 |
| DOI: | 10.1016/j.dnarep.2015.04.002 |
| Popis: | ERCC1-XPF is a structure-specific endonuclease that is required for the repair of DNA lesions, generated by the widely used platinum-containing cancer chemotherapeutics such as cisplatin, through the Nucleotide Excision Repair and Interstrand Crosslink Repair pathways. Based on mouse xenograft experiments, where ERCC1-deficient melanomas were cured by cisplatin therapy, we proposed that inhibition of ERCC1-XPF could enhance the effectiveness of platinum-based chemotherapy. Here we report the identification and properties of inhibitors against two key targets on ERCC1-XPF. By targeting the ERCC1-XPF interaction domain we proposed that inhibition would disrupt the ERCC1-XPF heterodimer resulting in destabilisation of both proteins. Using in silica screening, we identified an inhibitor that bound to ERCC1-XPF in a biophysical assay, reduced the level of ERCC1-XPF complexes in ovarian cancer cells, inhibited Nucleotide Excision Repair and sensitised melanoma cells to cisplatin. We also utilised high throughput and in silica screening to identify the first reported inhibitors of the other key target, the XPF endonuclease domain. We demonstrate that two of these compounds display specificity in vitro for ERCC1-XPF over two other endonucleases, bind to ERCC1-XPF, inhibit Nucleotide Excision Repair in two independent assays and specifically sensitise Nucleotide Excision Repair-proficient, but not Nucleotide Excision Repair-deficient human and mouse cells to cisplatin. (C) 2015 Elsevier BA/. All rights reserved. |
| Databáze: | OpenAIRE |
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