Download MendeleyBinary complex crystal structure of DNA polymerase beta reveals multiple conformations of the templating 8-oxoguanine lesion
Batra, V.K., Shock, D.D., Beard, W.A., McKenna, C.E., Wilson, S.H.(2012) Proc Natl Acad Sci U S A 109: 113-118
- PubMed: 22178760
- DOI: https://doi.org/10.1073/pnas.1112235108
- Primary Citation of Related Structures:
3RJE, 3RJF, 3RJG, 3RJH, 3RJI, 3RJJ, 3RJK - PubMed 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) ¦Â 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 ¦Â 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 ¦Â 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.
Organizational Affiliation:
Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709-2233, USA.
