Thymines opposite to bulky aristolactam-DNA adducts in duplex DNA are not targeted by human thymine-DNA glycosylase
Manapkyzy D. Zhamanbayeva G. Sidorenko V. Bonala R. Johnson F. Matkarimov B.T. Zharkov D. Saparbaev M.K. Taipakova S.
2025PeerJ Inc.
PeerJ
2025#13
Background: Consumption of aristolochic acids (AA) from the plant Aristolochia results in the formation of bulky aristolactam-dA (dA-AL) and aristolactam-dG (dG-AL) adducts in cellular DNA ultimately leading to the development of urothelial cancer. Intriguingly, the dA-AL adducts induce A•T→T•A transversions in tumor cells preferentially in CpA*→TpG context. The human mismatch-specific thymine-DNA glycosylase (TDG) protects cells against mutagenesis induced by spontaneous deamination of 5-methylcytosine (5mC) by removing thymine opposite to guanine in a CpG context in the base excision repair (BER) pathway. Nevertheless, challenges for DNA glycosylases to the faithful discrimination between non-damaged and damaged DNA strands do exist, such as mismatched pairs between two canonical bases, which may result due to DNA polymerase errors during replication. Previously, we demonstrated that TDG is prone to aberrant excision of T opposite to damaged adenine in duplex DNA in CpA*/TpG context. Methods: In the present work, using in vitro reconstitution assays, we investigated whether TDG participates in the aberrant removal of thymine opposite to dA-AL adducts in duplex DNA. Results: We have demonstrated that TDG either does not excise thymine or does so with extremely low efficiency when it is paired with dA-AL or dG-ALII adducts in duplex DNA. At the same time, TDG excises with high efficiency thymine opposite to guanine and hypoxanthine in T•G and T•Hx mispairs. Discussion: These findings strongly suggest that the human TDG is not involved in the aberrant DNA repair of AA-induced DNA damage. Copyright 2025 Manapkyzy et al.
Aberrant DNA repair , Aristolactam-guanine adduct , Aristolactamadenine adduct , Aristolochic acid , Base excision repair , DNA glycosylase , DNA repair , Mutational signature , T to A transversions , Thymine-DNA glycosylase
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Scientific Research Institute of Biology and Biotechnology Problems, Al-Farabi Kazakh National University, Almaty, Kazakhstan
Department of Molecular Biology and Genetics, Faculty of Biology and Biotechnology, Al-Farabi Kazakh National University, Almaty, Kazakhstan
Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY, United States
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY, United States
L. N. Gumilev Eurasian National University, Astana, Kazakhstan
National Laboratory Astana, Nazarbayev University, Astana, Kazakhstan
Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russian Federation
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, The Russian Academy of Sciences, Novosibirsk, Russian Federation
Gustave Roussy Cancer Campus, UMR9019 CNRS, Université Paris-Saclay, Villejuif, France
Scientific Research Institute of Biology and Biotechnology Problems
Department of Molecular Biology and Genetics
Department of Pharmacological Sciences
Department of Chemistry
L. N. Gumilev Eurasian National University
National Laboratory Astana
Department of Natural Sciences
Institute of Chemical Biology and Fundamental Medicine
Gustave Roussy Cancer Campus
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