8oxoG:A Is Structurally Accommodated in the Nucleosome Core Particle, Yet Inaccessible to MUTYH-Initiated DNA Repair
Abstract
Eukaryotic genomic DNA is packaged into chromatin as nucleosomes, where it remains susceptible to reactive oxygen species (ROS) that generate the mutagenic lesion 8-oxo-7,8-dihydroguanine (8oxoG). While 8-oxoguanine DNA glycosylase 1 (OGG1) can initiate repair of 8oxoG base paired with C within the nucleosome core particle (NCP) in a position- dependent manner, it is unknown whether MutY homolog (MUTYH), the DNA glycosylase that excises misincorporated A opposite 8oxoG, can initiate repair of 8oxoG:A base pairs within NCPs. To address this, we combined cryo-EM, molecular dynamics (MD) simulations, and biochemical assays. We determined that MUTYH activity on nucleosomal 8oxoG:A is strongly suppressed, with detectable excision limited to the entry/exit region. Cryo-EM structures at four superhelical locations reveal that 8oxoG adopts the syn conformation and Hoogsteen base pairs with A, as in non-nucleosomal DNA, indicating that lesion presentation is not altered by the histone octamer. MD simulations further reveal that 8oxoG:A base pair dynamics and local DNA backbone perturbations are similar in nucleosomal and non-nucleosomal DNA. Together, these data establish that the NCP sterically excludes MUTYH from 8oxoG:A base pairs, making them largely inaccessible to MUTYH processing. This work ultimately provides mechanistic insight for the elevated G to T transversion rate observed in histone-bound DNA following oxidative stress.
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BibTeX
@article{vito20268oxoga,
title = {{8oxoG:A Is Structurally Accommodated in the Nucleosome Core Particle, Yet Inaccessible to MUTYH-Initiated DNA Repair}},
author = {Abigayle Vito and Justin Ling and Julia Ferrara and Caleb Jacques and Natacha Gillet and Roy González-Alemán and Yuya Qiu and Mohammad Hashemian and Carlos Trasviña-Arenas and Sheila David and Sarah Delaney and Emmanuelle Bignon and Bret Freudenthal},
journal = {Biomolecules},
year = {2026},
month = jul,
doi = {10.3390/biom16070999},
url = {https://hal.science/hal-05756754v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - 8oxoG:A Is Structurally Accommodated in the Nucleosome Core Particle, Yet Inaccessible to MUTYH-Initiated DNA Repair
AU - Abigayle Vito
AU - Justin Ling
AU - Julia Ferrara
AU - Caleb Jacques
AU - Natacha Gillet
AU - Roy González-Alemán
AU - Yuya Qiu
AU - Mohammad Hashemian
AU - Carlos Trasviña-Arenas
AU - Sheila David
AU - Sarah Delaney
AU - Emmanuelle Bignon
AU - Bret Freudenthal
PY - 2026
DA - 2026/07/08
JO - Biomolecules
DO - 10.3390/biom16070999
UR - https://hal.science/hal-05756754v1
AB - Eukaryotic genomic DNA is packaged into chromatin as nucleosomes, where it remains susceptible to reactive oxygen species (ROS) that generate the mutagenic lesion 8-oxo-7,8-dihydroguanine (8oxoG). While 8-oxoguanine DNA glycosylase 1 (OGG1) can initiate repair of 8oxoG base paired with C within the nucleosome core particle (NCP) in a position- dependent manner, it is unknown whether MutY homolog (MUTYH), the DNA glycosylase that excises misincorporated A opposite 8oxoG, can initiate repair of 8oxoG:A base pairs within NCPs. To address this, we combined cryo-EM, molecular dynamics (MD) simulations, and biochemical assays. We determined that MUTYH activity on nucleosomal 8oxoG:A is strongly suppressed, with detectable excision limited to the entry/exit region. Cryo-EM structures at four superhelical locations reveal that 8oxoG adopts the syn conformation and Hoogsteen base pairs with A, as in non-nucleosomal DNA, indicating that lesion presentation is not altered by the histone octamer. MD simulations further reveal that 8oxoG:A base pair dynamics and local DNA backbone perturbations are similar in nucleosomal and non-nucleosomal DNA. Together, these data establish that the NCP sterically excludes MUTYH from 8oxoG:A base pairs, making them largely inaccessible to MUTYH processing. This work ultimately provides mechanistic insight for the elevated G to T transversion rate observed in histone-bound DNA following oxidative stress.
SN - 2218-273X
ER -