Identification of Small Molecule Translesion Synthesis Inhibitors That Target the Rev1-CT/RIR Protein-Protein Interaction
Open accessAbstract
Translesion synthesis (TLS) is an important mechanism through which proliferating cells tolerate DNA damage during replication. The mutagenic Rev1/Polζ-dependent branch of TLS helps cancer cells survive first-line genotoxic chemotherapy and introduces mutations that can contribute to the acquired resistance so often observed with standard anticancer regimens. As such, inhibition of Rev1/Polζ-dependent TLS has recently emerged as a strategy to enhance the efficacy of first-line chemotherapy and reduce the acquisition of chemoresistance by decreasing tumor mutation rate. The TLS DNA polymerase Rev1 serves as an integral scaffolding protein that mediates the assembly of the active multiprotein TLS complexes. Protein-protein interactions (PPIs) between the C-terminal domain of Rev1 (Rev1-CT) and the Rev1-interacting region (RIR) of other TLS DNA polymerases play an essential role in regulating TLS activity. To probe whether disrupting the Rev1-CT/RIR PPI is a valid approach for developing a new class of targeted anticancer agents, we designed a fluorescence polarization-based assay that was utilized in a pilot screen for small molecule inhibitors of this PPI. Two small molecule scaffolds that disrupt this interaction were identified, and secondary validation assays confirmed that compound 5 binds to Rev1-CT at the RIR interface. Finally, survival and mutagenesis assays in mouse embryonic fibroblasts and human fibrosarcoma HT1080 cells treated with cisplatin and ultraviolet light indicate that these compounds inhibit mutagenic Rev1/Polζ-dependent TLS in cells, validating the Rev1-CT/RIR PPI for future anticancer drug discovery and identifying the first small molecule inhibitors of TLS that target Rev1-CT.
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Inhibiting the mutagenic branch of TLS by disrupting pol ζ and Rev1 protein interactions is a strategy.
“Another strategy is to inhibit the mutagenic branch of TLS by disrupting pol ζ and Rev1 protein interactions [118,119]”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [118]
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Human TLS DNA polymerase: saviors or threats under replication stress?
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A stapled POL κ peptide targets REV1 to inhibit mutagenic translesion synthesis
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Repair Mechanisms and Initiation in Carcinogenesis
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Protein–protein interaction inhibitors in the human proteome: lessons from 117 targeted interactions
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- Authors
- Sail, V., Rizzo, A. A., Chatterjee, N., Dash, R. C., Ozen, Z., Walker, G. C., Korzhnev, D. M., & Hadden, M. K.
- Affiliations
- University of Connecticut (US)
- UConn Health (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Korzhnev, Dmitry M.
- Hadden, M. Kyle
- ORCID
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-06-09
- Volume
- 12
- Issue
- 7
- Pages
- 1903-1912
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC5992617
- OpenAlex
- W2619596151
- Cited by
- 52
- References
- 55
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 6 · 2020: 14 · 2019: 8 · 2018: 3 · 2017: 2
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- National Institute of Environmental Health Sciences (P30 ES002109)
- Division of Molecular and Cellular Biosciences (1615866)
- University of Connecticut Research Foundation
- Connecticut Institute for Clinical and Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- translesion synthesis, Rev1, protein-protein interaction inhibitors, small molecule inhibitors, pol, DNA polymerase, DNA damage tolerance, chemoresistance, cisplatin, ultraviolet radiation, mutagenesis, fluorescence polarization assay, anticancer drug discovery
- MeSH terms
- Y-Family DNA Polymerases, Animals, Binding Sites, Cells, Cultured, DNA-Directed DNA Polymerase, DNA-Binding Proteins, Enzyme Activation, Humans, Models, Molecular, Nuclear Proteins, Nucleotidyltransferases, Proteins, Drug Delivery Systems, Nucleic Acid Synthesis Inhibitors, Inhibitory Concentration 50, Cell Line, Tumor, Mice, Small Molecule Libraries, Drug Discovery, Molecular Dynamics Simulation
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