Small-molecules that bind to the ubiquitin-binding motif of REV1 inhibit REV1 interaction with K164-monoubiquitinated PCNA and suppress DNA damage tolerance
Open accessAbstract
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.
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These compounds cannot achieve complete TLS inhibition.
“These compounds, however, cannot achieve complete TLS inhibition.”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [115]
Development of drugs interfering with different aspects of the TLS pathway was attempted with promising results.
“The development of drugs interfering with different aspects of the TLS pathway was also attempted with promising results [113,114,115,116]”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [115]
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A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy
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- Authors
- Vanarotti, M., Evison, B. J., Actis, M. L., Inoue, A., McDonald, E. T., Shao, Y., Heath, R. J., & Fujii, N.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Fujii, Naoaki
- Venue
- Bioorganic & Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 26
- Issue
- 9
- Pages
- 2345-2353
- ISSN
- 0968-0896 (ISSN-L)
- PMC
- PMC5935547
- OpenAlex
- W2791888533
- Cited by
- 17
- References
- 33
- Citations by year
- 2026: 1 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 7 · 2019: 4
- FWCI
- 1.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Bioorganic & Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- ALSAC
- The Cell & Tissue Imaging Center
- NCI (P30 CA021765-34)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- Rev1, DNA damage tolerance, PCNA monoubiquitination, small molecule inhibitors, protein-protein interaction inhibition, cisplatin, UV-induced DNA damage, HPRT mutations, clonogenic survival
- MeSH terms
- Y-Family DNA Polymerases, Binding Sites, Cisplatin, DNA, DNA Damage, Humans, Hypoxanthine Phosphoribosyltransferase, Lysine, Nuclear Proteins, Nucleotidyltransferases, Piperazines, Protein Binding, Ultraviolet Rays, Mutagenesis, Proliferating Cell Nuclear Antigen, Nuclear Magnetic Resonance, Biomolecular, Cell Line, Tumor, Ubiquitination
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