The finding of a novel small DNA lesion with high thermal resistance and stability under basic conditions

Taishu Kawada; Katsuhito Kino; Akito Komi; Haruna Nishiyama; Rina Tsuboi; Akane Sakaga; Mayu Araki; Masayuki Morikawa; Yasuko Okamoto; Yoshiyuki Tanaka; Kiyohiko Kawai; Mamoru Fujitsuka

doi:10.51094/jxiv.2070

##article.authors##

Taishu Kawada Department of Nano Material and Bio Engineering, Faculty of Science and Engineering, Tokushima Bunri University, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Graduate School of Biomedical and Health Sciences, Hiroshima University
Katsuhito Kino Department of Nano Material and Bio Engineering, Faculty of Science and Engineering, Tokushima Bunri University, Center for Advance Science and Engineering, Tokushima Bunri University
Akito Komi Department of Nano Material and Bio Engineering, Faculty of Science and Engineering, Tokushima Bunri University
Haruna Nishiyama Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University
Rina Tsuboi Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University
Akane Sakaga Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University
Mayu Araki Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University
Masayuki Morikawa Faculty of Pharmaceutical Sciences, Tokushima Bunri University
Yasuko Okamoto Faculty of Pharmaceutical Sciences, Tokushima Bunri University
Yoshiyuki Tanaka Faculty of Pharmaceutical Sciences, Tokushima Bunri University
Kiyohiko Kawai Department of Life Science and Technology, School of Life Science and Technology, Institute of Science Tokyo
Mamoru Fujitsuka SANKEN (The Institute of Scientific and Industrial Research), The University of Osaka

DOI:

https://doi.org/10.51094/jxiv.2070

キーワード:

small DNA lesion、 oxamic acid、 stability、 DNA polymerase、 base excision repair

抄録

DNA, which is a carrier of genetic information, can be damaged by various environmental factors. DNA damage causes mutations during DNA replication, whereas accurate DNA repair processes can prevent such mutations. Such DNA lesions are known to range in size from bulky to small. Compared with the kinds of bulky and moderate DNA lesions, those of small DNA lesions are fewer, because the loss of conjugated structures makes the molecules unstable. Therefore, discovering small DNA lesions are particularly challenging. Surprisingly, we identified a novel small lesion, oxamic acid (Oxm), which is produced under physiological conditions (pH 7.4, 37°C). Oxm exhibited remarkable stability at high temperatures and under basic conditions. Moreover, guanine was preferentially incorporated opposite Oxm by DNA polymerases, allowing a primer to be extended to full length across the lesion, and then Oxm showed the potential to induce G:C → C:G transversions. Despite this mutagenic potential, base excision repair enzymes cleaved DNA oligonucleotides containing Oxm; formamidopyrimidine-DNA glycosylase specifically recognized only the Oxm:C base pair. Based on these results, Oxm is unique relative to previously characterized lesions such as 8-oxoG and Oz, and then this lesion may play a role in the mechanisms underlying gene mutations.

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The authors declare no competing interest.

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引用文献

A.-M. Fleminga, J.-C. Dingmana, C.-J. Burrows, CO2 protects cells from iron-Fenton oxidative DNA damage in Escherichia coli and humans. Proc. Natl. Acad. Sci. U.S.A. 121, e2419175121 (2024).

D. Aerssens, E. Cadoni, L. Tack, A. Madder, A photosensitized singlet oxygen (1O2) toolbox for bio-organic applications: Tailoring 1O2 generation for DNA and protein labelling, targeting and biosensing. Molecules 27, 778 (2022).

K. Hirakawa, S. Okazaki, H. Murakami, N. Kanayama, Development of cancer-selective and effective photosensitizers through electron transfer mechanism. J. Jpn. Soc. Laser Surg. Med. 41, 349–355 (2021).

E. Dumont, A. Monari, Understanding DNA under oxidative stress and sensitization: The role of molecular modeling. Front. Chem. 3, 43 (2015).

B.-H. Yun, P.-C. Dedon, N.-E. Geacintov, V. Shafirovich, One-electron oxidation of a pyrenyl photosensitizer covalently attached to DNA and competition between its further oxidation and DNA hole injection. Photochem. Photobiol. 86, 563–570 (2010).

S. Kawanishi, Y. Hiraku, S. Oikawa, Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging Mutat. Res. 488, 65–76 (2001).

K. Kino et al., The oxidation of 8-oxo-7,8-dihydroguanine by iodine. Bioorg. Med. Chem. Lett. 20, 3818–3820 (2010).

S. Steenken, S.-V. Jovanovic, How easily oxidizable is DNA? One-electron reduction potentials of adenosine and guanosine radicals in aqueous solution. J. Am. Chem. Soc. 119, 617–618 (1997).

N. Liu, J. Du, J. Ge, S.-B. Liu, DNA damage-inducing endogenous and exogenous factors and research progress. Nucleosides Nucleotides Nucleic Acids 14, 1-33 (2024).

N. Kumar, S. Raja, B.-V. Houten, The involvement of nucleotide excision repair proteins in the removal of oxidative DNA damage. Nucleic Acids Res. 48, 11227-11243 (2020).

N.J. Sargentini, K.C. Smith, DNA sequence analysis of γ-radiation (anionic)-induced and spontaneous lacId mutations in Escherichia coli K-12. Mutat. Res. 309, 147–163 (1994).

C.-E. Halim, S. Deng, K.-C. Crasta, C.-T. Yap, Interplay between the cytoskeleton and DNA damage response in cancer progression. Cancers 17, 1378 (2025).

H.-E. Krokan, M. Bjøras, Base excision repair. Cold Spring Harb. Perspect. Biol. 5, a012583 (2013).

S. Zhao, S.-L. Habib, A.-G. Senejani, M. Sebastian, D. Kidane, Role of base excision repair in innate immune cells and its relevance for cancer therapy. Biomedicines 10, 557 (2022).

M. Kolbanovskiy, A. Aharonoff, A.-H. Sales, N.-E Geacintov, V. Shafirovich, Base and nucleotide excision repair pathways in DNA plasmids harboring oxidatively generated guanine lesions. Chem. Res. Toxicol. 34, 1, 154–160 (2021).

J. A. Marteijn, H. Lans, W. Vermeulen, J. H. Hoeijmakers, Understanding nucleotide excision repair and its roles in cancer and ageing. Nat. Rev. Mol. Cell Biol. 15, 465−481 (2014)

O,-D. Schärer, Nucleotide excision repair in eukaryotes. Cold Spring Harb Perspect Biol. 5, a012609, (2013).

P.-J. Berti, J.-A.-B. McCann, Toward a detailed understanding of base excision repair enzymes: Transition state and mechanistic analyses of N-Glycoside Hydrolysis and N-Glycoside Transfer. Chem. Rev. 106, 506−555 (2006).

E.C. Friedberg et al., DNA Repair and Mutagenesis, 2nd Edition, ASM Press, Washington, DC, (2005).

W. Zhou et al., Base excision repair in human cancer: Emerging diagnostic and therapeutic target. DNA Repair 152, 103879 (2025).

J.-A. Brinkman, Y. Liu, S.-J. Kron, Small-molecule drug repurposing to target DNA damage repair and response pathways. Semin. Cancer Biol. 68, 230–241 (2021).

H.-M. Khaled et al., Correlation between p53 mutations and HPV in bilharzial bladder cancer. Urol. Oncol. 21, 334−341 (2003).

F. Maehira et al., Alterations of protein kinase C, 8-hydroxydeoxyguanosine, and K-ras oncogene in rat lungs exposed to passive smoking. Clin. Chim. Acta. 289, 133−144 (1999).

W. Giaretti et al., Specific K-ras2 mutations in human sporadic colorectal adenomas are associated with DNA near-diploid aneuploidy and inhibition of proliferation. Am. J. Pathol. 153, 1201−1209 (1998).

O. Adebalia, A. Sancarc, C.-P. Selby, Dynamics of transcription- coupled repair of cyclobutane pyrimidine dimers and (6-4) photoproducts in Escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 121, e2416877121 (2024).

A.-H. Sales et al., Inhibition of E. coli RecQ helicase activity by structurally distinct DNA lesions: Structure—Function relationships. Int. J. Mol. Sci. 23, 15654 (2022).

L. Sarmini, N. Kitsera, M. Meabed, A. Khobta, Transcription blocking properties and transcription-coupled repair of N2-alkylguanine adducts as a model for aldehyde-induced DNA damage. J. Biol. Chem. 301, 108459 (2025).

M.-K. Tang et al., Reactions of [13C]-labelled tobacco smoke with DNA to generate selected adducts formed without metabolic activation. Carcinogenesis, 46, bgaf008 (2025).

Y. Chen, R.-E. Johnson, R.-A. Manderville, J. Liu, A high-affinity and selective DNA aptamer for the N-linked C8-deoxyguanosine adduct produced by the arylamine carcinogen 4-aminobiphenyl. Chem. Res. Toxicol. 38, 340−346 (2025).

M. Dylewska et al., AlkA glycosylase and AlkB dioxygenase constitute an effective protective system for endogenously arising acrolein. J. Mol. Biol. 437, 168912 (2025).

C.-K. Au, S. Nagl, W. Chan, Effects of heavy metal Co-exposure on the formation of DNA adducts from aristolochic acid I: Implications for balkan endemic nephropathy development. Chem. Res. Toxicol. 37, 545−548 (2024).

Y.-E.-R. Jeong, R.-W. Kung, J.-Bykowski, T.-K. Deak, S.-D. Wetmore, Effect of guanine adduct size, shape, and linker type on the conformation of adducted DNA: A DFT and molecular dynamics study. J. Phys. Chem. B 127, 9035−9049 (2023).

M. Bellamri et al., Nuclear DNA and mitochondrial damage of the cooked meat carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in human neuroblastoma cells. Chem. Res. Toxicol. 36, 1361−1373 (2023).

Y. Fu et al., Base-displaced intercalated structure of the 3-(2-deoxy-β-D-erythropentofuranosyl)-pyrimido[1,2-f]purine-6,10(3H,5H)-dione (6-oxo-M1dG) lesion in DNA. Chem. Res. Toxicol. 36, 1947−1960 (2023).

K.-Y. Wu et al., Dose-response formation of N7-(3-benzo[1,3]dioxol-5-yl-2-hydroxypropyl) guanine in liver and urine correlates with micronucleated reticulocyte frequencies in mice administered safrole oxide. Food Chem. Toxicol. 181, 114056 (2023).

P.-L. Li et al., An unprecedented free radical mechanism for the formation of DNA adducts by the carcinogenic N-sulfonated metabolite of aristolochic acids. Free Radic Biol. Med. 205, 332-345 (2023).

S.-S. Bagale et al., Synthesis of N2-trans-isosafrole-dG-adduct bearing DNAs and the bypass studies with human TLS polymerases κ and η. J. Org. Chem. 89, 7680−7691 (2024).

N.-A. Johnson, R. McKenzie, L. McLean, L.-C Sowers, H.-M Fletcher, 8-oxo-7,8-dihydroguanine is removed by a nucleotide excision repair-like mechanism in Porphyromonas gingivalis W83. J. Bacteriol. 186, 7697-7703 (2004).

S. Jang et al., UV-DDB stimulates the activity of SMUG1 during base excision repair of 5-hydroxymethyl-2'-deoxyuridine moieties. Nucleic Acids Res. 51, 4881-4898 (2023).

T. Sugiyama, M.-R. Sanyal, Biochemical analysis of H2O2-induced mutation spectra revealed that multiple damages were involved in the mutational process. DNA Repair 134, 103617 (2024).

A.-D. Stolyarenko, A.-A. Novikova, E.-S. Shilkin, V.-A. Poltorachenko, A.-V. Makarova, The catalytic activity of human REV1 on undamaged and damaged DNA. Int. J. Mol. Sci. 25, 4107 (2024).

A. Galli et al., Ligation-mediated polymerase chain reaction detection of 8-oxo-7,8-dihydro-2′-deoxyguanosine and 5-hydroxycytosine at the codon 176 of the p53 gene of hepatitis C-associated hepatocellular carcinoma patients. Int. J. Mol. Sci. 21, 6753 (2020).

M. Kolbanovskiy, A. Aharonoff, A.-H. Sales, N.-E. Geacintov, V. Shafirovich, Recognition and repair of oxidatively generated DNA lesions in plasmid DNA by a facilitated diffusion mechanism. Biochem. J. 478, 2359–2370 (2021).

P.-L. McKibbin et al., Repair of hydantoin lesions and their amine adducts in DNA by base and nucleotide excision repair. J. Am. Chem. Soc. 135, 13851−13861 (2013).

V. Shaﬁrovich, K. Kropachev, M. Kolbanovskiy, N.-E. Geacintov, Excision of oxidatively generated guanine lesions by competing base and nucleotide excision repair mechanisms in human cells. Chem. Res. Toxicol. 32, 753−761 (2019).

A.-H. Sales et al., Treatment of human HeLa cells with black raspberry extracts enhances the removal of DNA lesions by the nucleotide excision repair mechanism. Antioxidants, 11, 2110 (2022).

E.-R. Lotsof et al., NEIL1 recoding due to RNA editing impacts lesion-specific recognition and excision. J. Am. Chem. Soc. 144, 14578−14589 (2022).

M.-D. Leipold, J.-G. Muller, C.-J. Burrows, S.-S. David, Removal of hydantoin products of 8-oxoguanine oxidation by the Escherichia coli. Biochemistry 39, 14984-14992 (2000).

V. Duarte, J.-G. Muller, C.-J. Burrows, Insertion of dGMP and dAMP during in vitro DNA synthesis opposite an oxidized form of 7,8-dihydro-8-oxoguanine. Nucleic Acids Res. 27, 496-502 (1999).

H.-W. Servius, A.-C. Drohat, Characterizing the excision of 7,8-dihydro-8-oxoadenine by thymine DNA glycosylase. J. Biol. Chem. 301, 110363 (2025)

A.-L. Rozelle, Y. Cheun, C.-K. Vilas, M.-C. Koag, S. Lee, DNA interstrand cross-links induced by the major oxidative adenine lesion 7,8-dihydro-8-oxoadenine. Nat. Commun. 12, 1897 (2021).

J.-J. Mäkinen, P. Rosenqvist, P. Virta, M. Metsä-Ketelä, G.-A. Belogurov, Probing the nucleobase selectivity of RNA polymerases with dual-coding substrates. J. Biol. Chem. 300, 107755 (2024).

H. Jung, S. Lee, Promutagenic bypass of 7,8-dihydro-8-oxoadenine by translesion synthesis DNA polymerase Dpo4. Biochem. J. 477, 2859-2871 (2020).

M. Wojciechowski, H. Czapinska, J. Krwawicz, D. Rafalski, M. Bochtler, Cytosine analogues as DNA methyltransferase substrates. Nucleic Acids Res. 52, 9267-9281 (2024).

Y. Sakurai et al., Synthesis and properties of nucleobase-sugar dual modified nucleic acids: 2′-OMe-RNA and scpBNA bearing a 5-hydroxycytosine nucleobase. J. Org. Chem. 88, 154−162 (2023).

T. Yokogawa et al., dUTPase inhibition confers susceptibility to a thymidylate synthase inhibitor in DNA-repair-defective human cancer cells. Cancer Sci. 112, 422-432 (2021).

L.-A. Lipscomb et al., X-ray structure of a DNA decamer containing 7,8-dihydro-8-oxoguanine. Proc. Natl. Acad. Sci. U.S.A. 92, 719-723 (1995).

V.-K. Batra, D.-D. Shock, W.-A. Beard, C.-E. McKenna, S.-H. Wilson, Binary complex crystal structure of DNA polymerase β reveals multiple conformations of the templating 8-oxoguanine lesion. Proc. Natl. Acad. Sci. U.S.A. 109, 113-118 (2012).

C. Bryan, J. Cepeda, B. Li, K. Yang, DNA−protein cross-links derived from abasic DNA lesions: Recent progress and future directions. Chem. Res. Toxicol. 38, 997−1005 (2025).

C. Bryan, K. Yang, Human 8-Oxoguanine glycosylase OGG1 cleaves abasic sites and covalently conjugates to 3’-DNA termini via cysteine and histidine addition. ChemBioChem 26, e202400705 (2025).

R. Tomar, S. Li, M. Egli, M.-P. Stone, Replication bypass of the N-(2-deoxy-D-erythro-pentofuranosyl)-urea DNA lesion by human DNA polymerase η. Biochemistry, 63, 754−766 (2024).

R. Tomar et al., Base excision repair of the N-(2-deoxy-D-erythro-pentofuranosyl)-urea lesion by the hNEIL1 glycosylase. Nucleic Acids Res. 51, 3754-3769 (2023).

T. Kawada et al., Analysis of nucleotide insertion opposite urea and translesion synthesis across urea by DNA polymerases. Genes Environ. 44, 7 (2022).

B.-T. Karwowski, The influence of clustered DNA damage containing Iz/Oz and OXOdG on the charge transfer through the double helix: A theoretical study. Molecules, 29, 2754 (2024).

T. Suzuki, M. Takeuchi, A. Ozawa-Tamura, Reactions of 3′,5′-di-O-acetyl-2′-deoxyguansoine and 3′,5′-di-O-acetyl-2′-deoxyadenosine to UV light in the presence of uric acid. Genes Environ. 44, 4 (2022).

B.-Z. Zhu, M. Tang, C.-H. Huang, L. Mao, J. Shao, Mechanistic study on oxidative DNA damage and modiﬁcations by haloquinoid carcinogenic intermediates and disinfection byproducts. Chem. Res. Toxicol. 34, 1701−1712 (2021).

D. Hernández-Álvarez et al., Aging, physical exercise, telomeres, and sarcopenia: A narrative review. Biomedicines, 11, 598 (2023).

C.-M.-C. Andrés, J.-M.-P.-l. Lastra, C.-A. Juan, F.-J. Plou, E. Pérez-Lebeña, Chemical insights into oxidative and nitrative modiﬁcations of DNA. Int. J. Mol. Sci. 24, 15240 (2023).

D. Stathis, U. Lischke, S.-C. Koch, C.-A. Deiml, T. Carell, Discovery and mutagenicity of a guanidinoformimine lesion as a new intermediate of the oxidative deoxyguanosine degradation pathway. J. Am. Chem. Soc. 134, 4925−4930 (2012).

Y. Sato et al., Synthetic DNA binders for fluorescent sensing of thymine glycol-containing DNA duplexes and inhibition of endonuclease activity. Chem. Commun. 59, 6088 (2023).

S. Delaney, J.-C. Delaney, J.-M. Essigmann, Chemical-biological ﬁngerprinting: Probing the properties of DNA lesions formed by peroxynitrite. Chem. Res. Toxicol. 20, 1718-1729 (2007).

V. Duarte, D. Gasparutto, M. Jaquinod, J. Cadet, In vitro DNA synthesis opposite oxazolone and repair of this DNA damage using modiﬁed oligonucleotides. Nucleic Acids Res. 28, 1555-1563 (2000).

J. Cadet et al., 2,2-Diamino-4-[(3,5-di-O-acetyl-2-deoxy-β-D-erythro-pentofuranosyl)amino]-5-(2H)-oxazolone: a novel and predominant radical oxidation product of 3′,5′-di-O-acetyl-2′-deoxygua-nosine. J. Am. Chem. Soc. 116, 7403-7404 (1994).

I.-G. Shishkina, F. Johnson, A new method for the postsynthetic generation of abasic sites in oligomeric DNA. Chem. Res. Toxicol. 13, 907–912 (2000).

K. Kino et al., Eukaryotic DNA polymerases α, β and ε incorporate guanine opposite 2,2,4-triamino-5(2H)-oxazolone. ChemBioChem 10, 2613-2616 (2009).

M. Suzuki et al., Contiguous 2,2,4-triamino-5(2H)-oxazolone obstructs DNA synthesis by DNA polymerases α, β, η, ι, κ, REV1 and Klenow fragment exo-, but not by DNA polymerase ζ. J. Biochem. 159, 323-329 (2016).

M. Suzuki et al., Analysis of nucleotide insertion opposite 2,2,4-triamino-5(2H)-oxazolone by eukaryotic B- and Y-family DNA polymerases. Chem. Res. Toxicol. 28, 1307-1316 (2015).

M. Suzuki et al., Effects of stability of base pairs containing an oxazolone on DNA elongation. J. Nucleic Acids 178350 (2014).

K. Takimoto et al., Delayed transfection of DNA after riboﬂavin mediated photosensitization increases G:C to C:G transversions of supF gene in Escherichia coli mutY strain. Mutat. Res. 445, 93–98 (1999).

I. Schulz, H.-C. Mahler, S. Boiteux, B. Epe, Oxidative DNA base damage induced by singlet oxygen and photosensitization: recognition by repair endonucleases and mutagenicity. Mutat. Res. 461, 145–156 (2000).

T.-J. Macbride, B.-D. Preston, L.-A. Loeb, Mutagenic spectrum resulting from DNA damage by oxygen radicals. Biochemistry 30, 207–213 (1991).

S. Akasaka, K. Takimoto, Hydrogen peroxide induces G:C to T:A and G:C to C:G transversions in the supF gene of Es-cherichia coli. Mol. Gen. Genet. 243, 500–505 (1994).

M.-R. Valentine, H. Rodriguez, J. Termini, Mutagenesis by peroxy radical is dominated by transversions at deoxyguanosine: Evidence for the lack of involvement of 8-oxo-dG and/or abasic site formation. Biochemistry 37, 7030–7038 (1998).

C.-Y. Shin, O.-N. Ponomareva, L. Connolly, M.-S. Turker, A mouse kidney cell line with a G:C→C:G transversion mutator phenotype. Mutat. Res. 503, 69–76 (2002).

K. Tano, Y. Iwamatsu, S. Yasuhira, H. Utsumi, K. Takimoto, Increased base change mutations at G:C pairs in Escherichia coli deficient in endonuclease III and VIII. J. Radiat. Res. 42, 409-413 (2001).

P. Rebecca et al., Fluorescence detection of 8-oxoguanine in nuclear and mitochondrial DNA of cultured cells using a recombinant Fab and confocal scanning laser microscopy. Free Radic Biol. Med. 28, 987-998 (2000).

T. Finkel, N.-J. Holbrook, Oxidants, oxidative stress and the biology of ageing. Nature 408, 239–247 (2000).

K. Kuroda et al., Possible contribution of 8-hydroxydeoxyguanosine to gene mutations in the kidney DNA of gpt delta rats following potassium bromate treatment. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 894, 503729 (2024).

S. Shibutani, M. Takeshita, A. P. Grollman, Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature 349, 431−434 (1991).

B. Matter, D. Malejka-Giganti, A.-S. Csallany, N. Tretyakova, Quantitative analysis of the oxidative DNA lesion, 2,2-diamino-4-(2-deoxy-β-D-erythro-pentofuranosyl)amino]-5(2H)-oxazolone (oxazolone), in vitro and in vivo by isotope dilution-capillary HPLC-ESI-MS/MS. Nucleic Acids Res. 34, 5449-5460 (2006).

A.-M. Fleming, O. Alshykhly, J. Zhu, J.-G. Muller, C.-J. Burrows. Rates of chemical cleavage of DNA and RNA oligomers containing guanine oxidation products. Chem. Res. Toxicol. 28, 1292-1300 (2015).

M.-E. Johansen, J.-G. Muller, X. Xu, C.-J. Burrows, Oxidatively induced DNA-protein cross-linking between single-stranded binding protein and oligodeoxynucleotides containing 8-oxo-7,8-dihydro-2′-deoxyguanosine. Biochemistry 44, 5660-5671 (2005).

K. Nakatani, J. Shirai, S. Sando, I. Saito, Guanine specific DNA cleavage by photoirradiation of dibenzoyldiazomethane−oligonucleotide conjugates. J. Am. Chem. Soc. 119, 7626–7635 (1997).

A.-M. Maxam, W. Gilbert, Sequencing end-labeled DNA with base-specific chemical cleavaes. Methods Enzymol. 65, 499-560 (1980).

M. Suzuki et al., Calculation of the stabilization energies of oxidatively damaged guanine base pairs with guanine Molecules 17, 6705-6715 (2012).

N.-R. Jena, P.-C. Mishra, Normal and reverse base pairing of Iz and Oz lesions in DNA: structural implications for mutagenesis. RSC Adv. 6, 64019 (2016).

A. Morrison, H. Araki, A.-B. Clark, R.-K. Hamatake, A. Sugino, A third essential DNA polymerase in S. cerevisiae. Cell, 62, 1143–1151 (1990).

M. Simon, L. Giot, G. Faye, DNA polymerase delta subunit of Saccharomyces cerevisiae is required for accurate replication. EMBO J. 10, 2165-2170 (1991).

A.-L. Morrison, A.-L. Johnson, L.-H. Johnston, A. Sugino, Pathway correcting DNA replication errors in Saccharomyces cerevisiae. EMBO J. 12, 1467-1473 (1993).

A. Morrison, A. Sugino, The 3′ → 5′ exonucleases of both DNA polymerases δ and ε participate in correcting errors of DNA replication in Saccharomyces cerevisiae. Mol. Gen. Genet. 242, 289-296 (1994).

A.-A.-L. Ler, M.-P. Carty, DNA damage tolerance pathways in human cells: A potential therapeutic target. Front. Oncol. 11, 822500 (2022).

C.-M. Kondratick, M.-T. Washington, M. Spies, Making choices: DNA replication fork recovery mechanisms. Semin. Cell Dev. Biol. 113, 27-37 (2021)

F. Yuan et al., Specificity of DNA lesion bypass by the yeast DNA polymerase η. J. Biol. Chem. 275, 8233-8239 (2000).

T. Matsuda, K. Bebenek, C. Masutani, F. Hanaoka, T.-A. Kunkel, Low fidelity DNA synthesis by human DNA polymerase η. Nature 404, 1011-1013 (2000).

C. Li et al., A sophisticated mechanism governs Pol ζ activity in response to replication stress. Nat. Commun. 15, 7562 (2024).

J.-R Nelson, C.-W Lawrence, D.-C Hinkle, Thymine-thymine dimer bypass by yeast DNA polymerase zeta. Science., 272, 1646-1649 (1996).

F. Zhu, M. Zhang, DNA polymerase ζ: new insight into eukaryotic mutagenesis and mammalian embryonic development. World J. Gastroenterol. 9, 1165-1169 (2003).

C.-W. Lawrence, Cellular roles of DNA polymerase ζ and Rev1 protein. DNA Repair (Amst) 1, 425-435 (2002).

C.-W. Lawrence, Cellular functions of DNA polymerase ζ and Rev1 protein. Adv. Protein Chem. 69, 167-203 (2004).

D. Guo, X. Wu, D. K.-Rajpal, J.-S. Taylor, Z. Wang, Translesion synthesis by yeast DNA polymerase ζ from templates containing lesions of ultraviolet radiation and acetylaminofluorene. Nucleic Acids Res. 29, 2875-2883 (2001).

L. Haracska, S. Prakash, L. Prakash, Yeast DNA polymerase ζ is an efficient extender of primer ends opposite from 7,8-dihydro-8-oxoguanine and O6-methylguanine. Mol. Cell. Biol. 23, 1453-1459 (2003).

J.-R. Nelson, C.-W. Lawrence, D.-C. Hinkle, Deoxycytidyl transferase activity of yeast REV1 protein. Nature 382, 729-731 (1996).

C. Masutani, R. Kusumoto, S. Iwai, F. Hanaoka, Mechanisms of accurate translesion synthesis by human DNA polymerase η. EMBO J. 19, 3100-3109 (2000).

A. Vaisman, C. Masutani, F. Hanaoka, S.-G. Chaney, Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase η. Biochemistry 39, 4575-4580 (2000).

L. Haracska, S.-L. Yu, R.-E. Johnson, L. Prakash, S. Prakash, Efficient and accurate replication in the presence of 7,8-dihydro-8-oxoguanine by DNA polymerase η. Nat. Genet. 25, 458-461 (2000).

L. Haracska, S. Prakash, L. Prakash, Translesion synthesis by human DNA polymerase η across oxidative products of guanine. Nucleic Acids Symp. Ser. 48 171-172 (2004).

X. Zhong et al., The fidelity of DNA synthesis by yeast DNA polymerase zeta alone and with accessory proteins. Nucleic Acids Res. 34, 4731–4742 (2001).

P. Garg, C.-M. Stith, J. Majka, P.-M. Burgers, Proliferating cell nuclear antigen promotes translesion synthesis by DNA polymerase zeta. J. Biol. Chem. 280, 23446–23450 (2005).

A. Katafuchi et al., Differential specificity of human and Escherichia coli Endonuclease III and VIII homologues for oxidative base lesions. J. Biol. Chem. 279, 14464-14471 (2004).

J. Tchou et al., 8-oxoguanine (8-hydroxyguanine) DNA glycosylase and its substrate specificity. Proc. Natl. Acad. Sci. U.S.A. 88, 4690-4694 (1991).

J.-C. Fromme, G.-L. Verdine, DNA lesion recognition by the bacterial repair enzyme MutM. J. Bio. Chem. 278, 51543-51548 (2003).

S.-D. Bruner, D.-P.-G. Norman, G.-L. Verdine, Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature 403, 859–866 (2000).

H. Kang et al., Advances in DNA damage detection: Current progress, challenges, and future directions. Trends Analyt. Chem. 189, 118246 (2025).

S. Sharma, C.-M. Helchowski, C.-E. Canman, Differential roles for DNA polymerases eta, zeta, and REV1 in lesion bypass of intrastrand versus interstrand DNA cross-links. Mutat. Res. 743–744, 97–110 (2013).

E.-S. Shilkin et al., Methylation and hydroxymethylation of cytosine alter activity and fidelity of translesion DNA polymerases. DNA Repair 141, 103712 (2024).

K. Chan, M.-A. Resnick, D.-A. Gordenin, The choice of nucleotide inserted opposite abasic sites formed within chromosomal DNA reveals the polymerase activities participating in translesion DNA synthesis. DNA Repair 12, 878-889 (2013).

J. Piao, Y. Masuda, K. Kamiya, Specific amino acid residues are involved in substrate discrimination and template binding of human REV1 protein. Biochem. Biophys. Res. Commun. 392, 140−144 (2010).

R.-K. Hamatake et al., Purification and characterization of DNA polymerase II from the yeast Saccharomyces cerevisiae. Identification of the catalytic core and a possible holoenzyme form of the enzyme. J. Biol. Chem. 265, 4072-83 (1990).

T. Kawada, M. Maehara, K. Kino, Increased yields of the guanine oxidative damage product imidazolone following exposure to LED light. Reactions 4, 801-810 (2023).

K. Kawai, A. Maruyama, Triple helix conformation-specific blinking of Cy3 in DNA. Chem. Commun. 51, 4861 (2015).