10GK

Nucleosome containing an 8oxoG:A at SHL+4

Summary for 10GK

• Entry DOI: 10.2210/pdb10gk/pdb
• EMDB information: 75153
• Descriptor: Histone H3.2, Histone H4, Histone H2A type 1, ... (6 entities in total)
• Functional Keywords: nucleosome, 8oxog, dna repair, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 10
• Total formula weight: 199423.70

Authors

Vito, A.F.,Ling, J.A.,Freudenthal, B.D. (deposition date: 2026-01-19, release date: 2026-07-22, Last modification date: 2026-08-12)

Primary citation

Vito, A.F.,Ling, J.A.,Ferrara, J.C.,Jacques, C.S.,Gillet, N.,Gonzalez-Aleman, R.,Qiu, Y.,Hashemian, M.,Trasvina-Arenas, C.H.,David, S.S.,Delaney, S.,Bignon, E.,Freudenthal, B.D.
8oxoG:A Is Structurally Accommodated in the Nucleosome Core Particle, Yet Inaccessible to MUTYH-Initiated DNA Repair.
Biomolecules, 16:-, 2026

PubMed 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 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.

PubMed: 42509793
DOI: 10.3390/biom16070999

Experimental method

ELECTRON MICROSCOPY (2.7 Å)