1U45: 8oxoguanine At The Pre-Insertion Site Of The Polymerase Active Site

Aerobic respiration generates reactive oxygen species that can damage guanine residues and lead to the production of 8-oxoguanine (8oxoG), the major mutagenic oxidative lesion in the genome. Oxidative damage is implicated in ageing and cancer, and its prevalence presents a constant challenge to DNA polymerases that ensure accurate transmission of genomic information. When these polymerases encounter 8oxoG, they frequently catalyse misincorporation of adenine in preference to accurate incorporation of cytosine. This results in the propagation of G to T transversions, which are commonly observed somatic mutations associated with human cancers. Here, we present sequential snapshots of a high-fidelity DNA polymerase during both accurate and mutagenic replication of 8oxoG. Comparison of these crystal structures reveals that 8oxoG induces an inversion of the mismatch recognition mechanisms that normally proofread DNA, such that the 8oxoG.adenine mismatch mimics a cognate base pair whereas the 8oxoG.cytosine base pair behaves as a mismatch. These studies reveal a fundamental mechanism of error-prone replication and show how 8oxoG, and DNA lesions in general, can form mismatches that evade polymerase error-detection mechanisms, potentially leading to the stable incorporation of lethal mutations.
PDB ID: 1U45Download
MMDB ID: 103158
PDB Deposition Date: 2004/7/23
Updated in MMDB: 2012/09
Experimental Method:
x-ray diffraction
Resolution: 2.01  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 1U45: trimeric; determined by author
Molecular Components in 1U45
Label Count Molecule
Protein (1 molecule)
DNA Polymerase I
Molecule annotation
Nucleotides(2 molecules)
DNA Primer Strand
Molecule annotation
DNA Template Strand With 8-oxoguanine
Molecule annotation
Chemicals (5 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB