Binary complex crystal structure of DNA polymerase β reveals multiple conformations of the templating 8-oxoguanine lesion

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Abstract

Oxidation of genomic DNA forms the guanine lesion 7,8-dihydro-8-oxoguanine (8-oxoG). When in the template base position during DNA synthesis the 8-oxoG lesion has dual coding potential by virtue of its anti- and syn-conformations, base pairing with cytosine and adenine, respectively. This impacts mutagenesis, because insertion of adenine opposite template 8-oxoG can result in a G to T transversion. DNA polymerases vary by orders of magnitude in their preferences for mutagenic vs. error-free 8-oxoG lesion bypass. Yet, the structural basis for lesion bypass specificity is not well understood. The DNA base excision repair enzyme DNA polymerase (pol) β is presented with gap-filling synthesis opposite 8-oxoG during repair and has similar insertion efficiencies for dCTP and dATP. We report the structure of pol β in binary complex with template 8-oxoG in a base excision repair substrate. The structure reveals both the syn- and anti-conformations of template 8-oxoG in the confines of the polymerase active site, consistent with the dual coding observed kinetically for this enzyme. A ternary complex structure of pol β with the syn-8-oxoG:anti-A Hoogsteen base pair in the closed fully assembled preinsertion active site is also reported. The syn-conformation of 8-oxoG is stabilized by minor groove hydrogen bonding between the side chain of Arg283 and O8 of 8-oxoG. An adjustment in the position of the phosphodiester backbone 5′-phosphate enables 8-oxoG to adopt the syn-conformation.

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Batra, V. K., Shock, D. D., Beard, W. A., McKenna, C. E., & Wilson, S. H. (2012). Binary complex crystal structure of DNA polymerase β reveals multiple conformations of the templating 8-oxoguanine lesion. Proceedings of the National Academy of Sciences of the United States of America, 109(1), 113–118. https://doi.org/10.1073/pnas.1112235108

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