1. Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA
2. Department of Chemistry and Biochemistry, Ludwig Maximilians University Munich, Butenandtstrasse 5-13, D 81377 Munich, Germany

Correspondence to: Lorena S. Beese¹ Email: lsb@biochem.duke.edu
Coordinates have been deposited in the Protein Data Bank under accession codes 1U45, 1U47, 1U48, 1U49 and 1U4B.

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 genome¹. Oxidative damage is implicated in ageing² 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 cytosine³. This results in the propagation of G to T transversions, which are commonly observed somatic mutations associated with human cancers^{4, 5}. 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 8oxoGadenine mismatch mimics a cognate base pair whereas the 8oxoGcytosine 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.

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.