ArticleProceedings of the National Academy of Sciences of the United States of America2015
Enzyme mechanism-based, oxidative DNA-protein cross-links formed with DNA polymerase β in vivo.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 65 citations in OpenAlex.
- Living Cells Employ Ubiquitin-Proteasomal System and Nucleotide Excision Repair Pathways to Remove Reactive Oxygen Species-Induced DNA-Protein Crosslinks (ROS-DPCs).bioRxiv : the preprint server for biology · 2026Article
- Long-Patch Base Excision Repair of 5'-DNA-Peptide Cross-Links Derived from Abasic DNA Lesions.Biochemistry · 2026Article
- Dirty Ends: Formation, Repair, and Biological Relevance of Non-Canonical DNA Terminal Structures.Genes · 2025Review
- CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair.Nature communications · 2025Article
- SPRTN metalloprotease participates in repair of ROS-mediated DNA-protein crosslinks.Scientific reports · 2024Article
- Isolation and detection of DNA-protein crosslinks in mammalian cells.Nucleic acids research · 2024Article
- Enzymatic Processing of DNA-Protein Crosslinks.Genes · 2024Review
- Human TDP1, APE1 and TREX1 repair 3'-DNA-peptide/protein cross-links arising from abasic sites in vitro.Nucleic acids research · 2022Article
- Targeting DNA-Protein CrosslinksFrontiers in molecular biosciences · 2022Review
- Mechanisms and Regulation of DNA-Protein Crosslink Repair During DNA Replication by SPRTN Protease.Frontiers in molecular biosciences · 2022Review
- Replication-dependent cytotoxicity and Spartan-mediated repair of trapped PARP1-DNA complexes.Nucleic acids research · 2021Article
- High-Resolution Mapping of Amino Acid Residues in DNA-Protein Cross-Links Enabled by Ribonucleotide-Containing DNA.Analytical chemistry · 2021Article
- Topoisomerase Assays.Current protocols · 2021Article
- DNA-protein crosslinks are repaired via homologous recombination in mammalian mitochondria.DNA repair · 2021Article
- Synthesis and polymerase bypass studies of DNA-peptide and DNA-protein conjugates.Methods in enzymology · 2021Article
- Understanding APE1 cellular functions by the structural preference of exonuclease activities.Computational and structural biotechnology journal · 2021Review
- Rapid, direct detection of bacterial topoisomerase 1-DNA adducts by RADAR/ELISA.Analytical biochemistry · 2020Article
- How to fix DNA-protein crosslinks.DNA repair · 2020Article
- DNA Structure-Specific Cleavage of DNA-Protein Crosslinks by the SPRTN Protease.Molecular cell · 2020Article
- Structural biology of DNA abasic site protection by SRAP proteins.DNA repair · 2020Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Free radical attack on the C1' position of DNA deoxyribose generates the oxidized abasic (AP) site 2-deoxyribonolactone (dL). Upon encountering dL, AP lyase enzymes such as DNA polymerase β (Polβ) form dead-end, covalent intermediates in vitro during attempted DNA repair. However, the conditions that lead to the in vivo formation of such DNA-protein cross-links (DPC), and their impact on cellular functions, have remained unknown. We adapted an immuno-slot blot approach to detect oxidative Polβ-DPC in vivo. Treatment of mammalian cells with genotoxic oxidants that generate dL in DNA led to the formation of Polβ-DPC in vivo. In a dose-dependent fashion, Polβ-DPC were detected in MDA-MB-231 human cells treated with the antitumor drug tirapazamine (TPZ; much more Polβ-DPC under 1% O2 than under 21% O2) and even more robustly with the "chemical nuclease" 1,10-copper-ortho-phenanthroline, Cu(OP)2. Mouse embryonic fibroblasts challenged with TPZ or Cu(OP)2 also incurred Polβ-DPC. Nonoxidative agents did not generate Polβ-DPC. The cross-linking in vivo was clearly a result of the base excision DNA repair pathway: oxidative Polβ-DPC depended on the Ape1 AP endonuclease, which generates the Polβ lyase substrate, and they required the essential lysine-72 in the Polβ lyase active site. Oxidative Polβ-DPC had an unexpectedly short half-life (∼ 30 min) in both human and mouse cells, and their removal was dependent on the proteasome. Proteasome inhibition under Cu(OP)2 treatment was significantly more cytotoxic to cells expressing wild-type Polβ than to cells with the lyase-defective form. That observation underscores the genotoxic potential of oxidative Polβ-DPC and the biological pressure to repair them.
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