6E3V

Structure of human DNA polymerase beta complexed with 8OA in the template base paired with incoming non-hydrolyzable TTP

Summary for 6E3V

• Entry DOI: 10.2210/pdb6e3v/pdb
• Related: 4XK3 4XK6 4XK7
• Descriptor: DNA polymerase beta, DNA (5'-D(*CP*CP*GP*AP*CP*(A38) P*TP*CP*GP*CP*AP*TP*CP*AP*GP*C)-3'), DNA (5'-D(*GP*CP*TP*GP*AP*TP*GP*CP*GP*A)-3'), ... (8 entities in total)
• Functional Keywords: dna polymerase, transferase-dna complex, dna binding protein, dna binding protein-dna complex, dna binding protein/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 48282.65

Authors

Koag, M.-C.,Lee, S. (deposition date: 2018-07-15, release date: 2019-04-03, Last modification date: 2023-10-11)

Primary citation

Koag, M.C.,Jung, H.,Lee, S.
Mutagenic Replication of the Major Oxidative Adenine Lesion 7,8-Dihydro-8-oxoadenine by Human DNA Polymerases.
J. Am. Chem. Soc., 141:4584-4596, 2019

PubMed 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.

PubMed: 30817143
DOI: 10.1021/jacs.8b08551

Experimental method

X-RAY DIFFRACTION (1.96 Å)