DNA Damage Recognition by Bacterial and Human Adenine-DNA Glycosylases: Insights from Non-Canonical Substrates
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.
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BibTeX
@article{sarsenbayeva2026damage,
title = {{DNA Damage Recognition by Bacterial and Human Adenine-DNA Glycosylases: Insights from Non-Canonical Substrates}},
author = {Ulan Sarsenbayeva and Didier Gasparutto and Nicolas Geacintov and Alexander A Ishchenko and Gulzhan Zhamanbayeva and Kamalidin O Sharipov and Carlos H Trasviña-Arenas and Sheila S David and Dmitry O Zharkov and Bakhyt T Matkarimov and Murat Saparbaev and Sabira Taipakova},
journal = {Biomolecules},
year = {2026},
month = aug,
doi = {10.3390/biom16081214},
url = {https://hal.science/hal-05740329v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - DNA Damage Recognition by Bacterial and Human Adenine-DNA Glycosylases: Insights from Non-Canonical Substrates
AU - Ulan Sarsenbayeva
AU - Didier Gasparutto
AU - Nicolas Geacintov
AU - Alexander A Ishchenko
AU - Gulzhan Zhamanbayeva
AU - Kamalidin O Sharipov
AU - Carlos H Trasviña-Arenas
AU - Sheila S David
AU - Dmitry O Zharkov
AU - Bakhyt T Matkarimov
AU - Murat Saparbaev
AU - Sabira Taipakova
PY - 2026
DA - 2026/08/20
JO - Biomolecules
DO - 10.3390/biom16081214
UR - https://hal.science/hal-05740329v1
AB - 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.
SN - 2218-273X
ER -