DNA Damage Recognition by Bacterial and Human Adenine-DNA Glycosylases: Insights from Non-Canonical Substrates

The Escherichia coli adenine-DNA glycosylase (MutY) and its human homologue, MUTYH, protect cells against oxygen-free radical-induced mutagenesis by excising regular adenine impaired with 8-oxo-7,8-dihydro-guanine (8oxoG) in the base excision repair (BER) pathway. However, removal of adenine by MutY and MUTYH from an A·8oxoG pair generated via misincorporation of an oxidized nucleotide during DNA synthesis might induce A·T→C·G transversions. Here, to examine MutY and MUTYH in vitro activities, we used short synthetic DNA duplexes in which the target adenine residue was positioned opposite a variety of DNA base modifications. MUTYH does not excise mismatched adenine in non-canonical DNA substrates, whereas MutY excises adenine mispaired with 1,3-d(GpNpG) cisplatin intra-strand crosslink. In addition, we characterized four MUTYH variants associated with cancer risk, which exhibit the following order of DNA glycosylase deficiency: WT ≥ G169D > G202E ≈ Y165C >> D222N. Human adenine-DNA glycosylase MUTYH and its mutant variants, contrary to bacterial MutY, are not prone to aberrant removal of regular adenine residues opposite modified residues in DNA duplexes. We hypothesize that E. coli MutY is prone to aberrant repair under certain conditions and that this may prevent incorporation of adenine opposite blocking lesions in the template strand.

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Publication Details

Journal
Biomolecules
Published
2026-08-20
DOI
https://doi.org/10.3390/biom16081214
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
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article

DNA Damage Recognition by Bacterial and Human Adenine-DNA Glycosylases: Insights from Non-Canonical Substrates

Bakhyt Matkarimov, Nicholas E. Geacintov, Kamalidin Sharipov, Sabira Taipakova et al.
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article

DNA Damage Recognition by Bacterial and Human Adenine-DNA Glycosylases: Insights from Non-Canonical Substrates

Bakhyt Matkarimov, Nicholas E. Geacintov, Kamalidin Sharipov, Sabira Taipakova, Sheila S. David, Murat K. Saparbaev, Alexander A. Ishchenko, Didier Gasparutto, Carlos H. Trasviña-Arenas, Dmitry O. Zharkov, Gulzhan Zhamanbayeva, Ulan Sarsenbayeva
article en

Abstract

The Escherichia coli adenine-DNA glycosylase (MutY) and its human homologue, MUTYH, protect cells against oxygen-free radical-induced mutagenesis by excising regular adenine impaired with 8-oxo-7,8-dihydro-guanine (8oxoG) in the base excision repair (BER) pathway. However, removal of adenine by MutY and MUTYH from an A·8oxoG pair generated via misincorporation of an oxidized nucleotide during DNA synthesis might induce A·T→C·G transversions. Here, to examine MutY and MUTYH in vitro activities, we used short synthetic DNA duplexes in which the target adenine residue was positioned opposite a variety of DNA base modifications. MUTYH does not excise mismatched adenine in non-canonical DNA substrates, whereas MutY excises adenine mispaired with 1,3-d(GpNpG) cisplatin intra-strand crosslink. In addition, we characterized four MUTYH variants associated with cancer risk, which exhibit the following order of DNA glycosylase deficiency: WT ≥ G169D > G202E ≈ Y165C >> D222N. Human adenine-DNA glycosylase MUTYH and its mutant variants, contrary to bacterial MutY, are not prone to aberrant removal of regular adenine residues opposite modified residues in DNA duplexes. We hypothesize that E. coli MutY is prone to aberrant repair under certain conditions and that this may prevent incorporation of adenine opposite blocking lesions in the template strand.

BiomoleculesVol. 16(8)
L. N. Gumilyov Eurasian National University (KZ), Centre National de la Recherche Scientifique (FR), Al-Farabi Kazakh National University (KZ), Novosibirsk State University (RU), Kazakh National Medical University (KZ), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), CEA Grenoble (FR), Institut de Recherche Interdisciplinaire de Grenoble (FR), Institute of Chemical Biology and Fundamental Medicine (RU), Institute of Plant Biology and Biotechnology (KZ), New York University (US), Nazarbayev University (KZ), Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (MX), University of California, Davis (US), Université Grenoble Alpes (FR)
Agence Nationale de la Recherche
Openalex Percentile: Top 16%
DNA Repair Mechanisms
DOIOpen Access PDFOpenAlex
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