PDBsum entry 6e3v

DNA binding protein/DNA

PDB id: 6e3v

Contents

Protein chain

326 a.a.

DNA/RNA

Ligands

1FZ

Metals

_MG ×2

_NA ×2

Waters ×196

References listed in PDB file

Key reference

• Title: Mutagenic replication of the major oxidative adenine lesion 7,8-Dihydro-8-Oxoadenine by human DNA polymerases.
• Authors: M.C.Koag, H.Jung, S.Lee.
• Ref.: J Am Chem Soc, 2019, 141, 4584-4596. [DOI no: 10.1021/jacs.8b08551]
• PubMed id: 30817143

Abstract

Reactive oxygen species attack DNA to produce 7,8-dihyro-8-oxoguanine (oxoG) and 7,8-dihydro-8-oxoadenine (oxoA) as major lesions. The structural basis for the mutagenicity of oxoG, which induces G to T mutations, is well understood. However, the structural basis for the mutagenic potential of oxoA, which induces A to C mutations, remains poorly understood. To gain insight into oxoA-induced mutagenesis, we conducted kinetic studies of human DNA polymerases β and η replicating across oxoA and structural studies of polβ incorporating dTTP/dGTP opposite oxoA. While polη readily bypassed oxoA, it incorporated dGTP opposite oxoA with a catalytic specificity comparable to that of correct insertion, underscoring the promutagenic nature of the major oxidative adenine lesion. Polη and polβ incorporated dGTP opposite oxoA ∼170-fold and ∼100-fold more efficiently than that opposite dA, respectively, indicating that the 8-oxo moiety greatly facilitated error-prone replication. Crystal structures of polβ showed that, when paired with an incoming dTTP, the templating oxoA adopted an anti conformation and formed Watson-Crick base pair. When paired with dGTP, oxoA adopted a syn conformation and formed a Hoogsteen base pair with Watson-Crick-like geometry, highlighting the dual-coding potential of oxoA. The templating oxoA was stabilized by Lys280-mediated stacking and hydrogen bonds. Overall, these results provide insight into the mutagenic potential and dual-coding nature of the major oxidative adenine lesion.