ArticleNucleic acids research2022
Division of labor within the DNA damage tolerance system reveals non-epistatic and clinically actionable targets for precision cancer medicine.
Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 28 citations in OpenAlex.
- Isocyanate-Modified Melatplatin(IV) Enhances Antitumor Efficacy via TCF4/COL6A3-Mediated Extracellular Matrix Remodeling and cGAS-STING Pathway Activation in Bladder Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Differential roles of Rad18 in repressing carcinogen- and oncogene-driven mutagenesisNAR cancer · 2026Article
- DNA polymerase kappa stabilized by Ptbp2 interacts with MRE11 and promotes genomic instability in leukemia.Cell death discovery · 2026Article
- An accurate cellular assay to determine pathogenicity of coding and noncoding variants in Lynch syndrome genes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Differential roles of Rad18 in repressing carcinogen- and oncogene-driven mutagenesisbioRxiv : the preprint server for biology · 2025Article
- Catalytic and noncatalytic functions of DNA polymerase κ in translesion DNA synthesis.Nature structural & molecular biology · 2025Article
- Molecular dependencies and genomic consequences of a global DNA damage tolerance defect.Genome biology · 2024Article
- Article
- Dual role of proliferating cell nuclear antigen monoubiquitination in facilitating Fanconi anemia-mediated interstrand crosslink repair.PNAS nexus · 2024Article
- USP9X-mediated REV1 deubiquitination promotes lung cancer radioresistance via the action of REV1 as a Rad18 molecular scaffold for cystathionine γ-lyase.Journal of biomedical science · 2024Article
- Is switching intravesical chemotherapeutic agents beneficial in short-term recurrent high-risk non-muscle-invasive bladder tumors? A 5-year retrospective study.BMC urology · 2024Article
- Mammalian life depends on two distinct pathways of DNA damage tolerance.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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Authors and funding
20 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.
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