Small-molecules that bind to the ubiquitin-binding motif of REV1 inhibit REV1 interaction with K164-monoubiquitinated PCNA and suppress DNA damage tolerance
| Autor: | Ezelle T. McDonald, Murugendra Vanarotti, Richard J. Heath, Youming Shao, Akira Inoue, Benny J. Evison, Naoaki Fujii, Marcelo Actis |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Hypoxanthine Phosphoribosyltransferase Ubiquitin binding DNA damage Ultraviolet Rays Clinical Biochemistry Pharmaceutical Science Biochemistry Piperazines Article Protein–protein interaction 03 medical and health sciences Cell Line Tumor Proliferating Cell Nuclear Antigen Drug Discovery medicine Humans Molecular Biology Nuclear Magnetic Resonance Biomolecular Cisplatin Binding Sites biology Chemistry Lysine Organic Chemistry Ubiquitination Nuclear Proteins DNA Small molecule Nucleotidyltransferases Proliferating cell nuclear antigen Chromatin Cell biology 030104 developmental biology Mutagenesis biology.protein Molecular Medicine REV1 medicine.drug DNA Damage Protein Binding |
| Zdroj: | Bioorganicmedicinal chemistry. 26(9) |
| ISSN: | 1464-3391 |
| Popis: | REV1 protein is a mutagenic DNA damage tolerance (DDT) mediator and encodes two ubiquitin-binding motifs (i.e., UBM1 and UBM2) that are essential for the DDT function. REV1 interacts with K164-monoubiquitinated PCNA (UbPCNA) in cells upon DNA-damaging stress. By using AlphaScreen assays to detect inhibition of REV1 and UbPCNA protein interactions along with an NMR-based strategy, we identified small-molecule compounds that inhibit the REV1/UbPCNA interaction and that directly bind to REV1 UBM2. In cells, one of the compound prevented recruitment of REV1 to PCNA foci on chromatin upon cisplatin treatment, delayed removal of UV-induced cyclopyrimidine dimers from nuclei, prevented UV-induced mutation of HPRT gene, and diminished clonogenic survival of cells that were challenged by cyclophosphamide or cisplatin. This study demonstrates the potential utility of a small-molecule REV1 UBM2 inhibitor for preventing DDT. |
| Databáze: | OpenAIRE |
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