8VWU

Nucleosome containing 8oxoG at SHL4

8VWU の概要

• エントリーDOI: 10.2210/pdb8vwu/pdb
• EMDBエントリー: 43600
• 分子名称: Histone H3.2, Histone H4, Histone H2A type 1, ... (6 entities in total)
• 機能のキーワード: nucleosome, ogg1, dna repair, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 10
• 化学式量合計: 199399.67

構造登録者

Weaver, T.M.,Ling, J.A.,Freudenthal, B.D. (登録日: 2024-02-02, 公開日: 2024-10-30, 最終更新日: 2025-05-28)

主引用文献

Cordero, C.,Mehta, K.P.M.,Weaver, T.M.,Ling, J.A.,Freudenthal, B.D.,Cortez, D.,Roberts, S.A.
Contributing factors to the oxidation-induced mutational landscape in human cells.
Nat Commun, 15:10722-10722, 2024

PubMed Abstract: 8-oxoguanine (8-oxoG) is a common oxidative DNA lesion that causes G > T substitutions. Determinants of local and regional differences in 8-oxoG-induced mutability across genomes are currently unknown. Here, we show DNA oxidation induces G > T substitutions and insertion/deletion (INDEL) mutations in human cells and cancers. Potassium bromate (KBrO)-induced 8-oxoGs occur with similar sequence preferences as their derived substitutions, indicating that the reactivity of specific oxidants dictates mutation sequence specificity. While 8-oxoG occurs uniformly across chromatin, 8-oxoG-induced mutations are elevated in compact genomic regions, within nucleosomes, and at inward facing guanines within strongly positioned nucleosomes. Cryo-electron microscopy structures of OGG1-nucleosome complexes indicate that these effects originate from OGG1's ability to flip outward positioned 8-oxoG lesions into the catalytic pocket while inward facing lesions are occluded by the histone octamer. Mutation spectra from human cells with DNA repair deficiencies reveals contributions of a DNA repair network limiting 8-oxoG mutagenesis, where OGG1- and MUTYH-mediated base excision repair is supplemented by the replication-associated factors Pol η and HMCES. Transcriptional asymmetry of KBrO-induced mutations in OGG1- and Pol η-deficient cells also demonstrates transcription-coupled repair can prevent 8-oxoG-induced mutation. Thus, oxidant chemistry, chromatin structures, and DNA repair processes combine to dictate the oxidative mutational landscape in human genomes.

PubMed: 39715760
DOI: 10.1038/s41467-024-55497-z

実験手法

ELECTRON MICROSCOPY (3 Å)