6VEZ

DNA Polymerase Mu, 8-oxorGTP:At Pre-Catalytic Ternary Complex, 20 mM Ca2+ (60 min)

6VEZ の概要

• エントリーDOI: 10.2210/pdb6vez/pdb
• 関連するPDBエントリー: 6VF7
• 分子名称: DNA-directed DNA/RNA polymerase mu, 1,2-ETHANEDIOL, DNA (5'-D(*CP*GP*GP*CP*AP*TP*AP*CP*G)-3'), ... (11 entities in total)
• 機能のキーワード: time-lapse crystallography, oxidized ribonucleotide insertion, dna polymerase mu, double strand break repair, replication
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 46439.06

構造登録者

Jamsen, J.A.,Wilson, S.H. (登録日: 2020-01-03, 公開日: 2021-09-01, 最終更新日: 2025-09-03)

主引用文献

Jamsen, J.A.,Sassa, A.,Perera, L.,Shock, D.D.,Beard, W.A.,Wilson, S.H.
Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair.
Nat Commun, 12:5055-5055, 2021

PubMed Abstract: Reactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is required for successful NHEJ in vivo. We previously showed that pol μ lacks discrimination against oxidized dGTP (8-oxo-dGTP), that can lead to mutagenesis, cancer, aging and human disease. Here we reveal the structural basis for proficient oxidized ribonucleotide (8-oxo-rGTP) incorporation during DSB repair by pol μ. Time-lapse crystallography snapshots of structural intermediates during nucleotide insertion along with computational simulations reveal substrate, metal and side chain dynamics, that allow oxidized ribonucleotides to escape polymerase discrimination checkpoints. Abundant nucleotide pools, combined with inefficient sanitization and repair, implicate pol μ mediated oxidized ribonucleotide insertion as an emerging source of widespread persistent mutagenesis and genomic instability.

PubMed: 34417448
DOI: 10.1038/s41467-021-24486-x

実験手法

X-RAY DIFFRACTION (1.875 Å)