Dynamics of 8-Oxoguanine in DNA: Decisive Effects of Base Pairing and Nucleotide Context

J Am Chem Soc. 2023 Mar 15;145(10):5613-5617. doi: 10.1021/jacs.2c11230. Epub 2023 Mar 2.

Abstract

8-Oxo-7,8-dihydroguanine (oxoG), an abundant DNA lesion, can mispair with adenine and induce mutations. To prevent this, cells possess DNA repair glycosylases that excise either oxoG from oxoG:C pairs (bacterial Fpg, human OGG1) or A from oxoG:A mispairs (bacterial MutY, human MUTYH). Early lesion recognition steps remain murky and may include enforced base pair opening or capture of a spontaneously opened pair. We adapted the CLEANEX-PM NMR protocol to detect DNA imino proton exchange and analyzed the dynamics of oxoG:C, oxoG:A, and their undamaged counterparts in nucleotide contexts with different stacking energy. Even in a poorly stacking context, the oxoG:C pair did not open easier than G:C, arguing against extrahelical base capture by Fpg/OGG1. On the contrary, oxoG opposite A significantly populated the extrahelical state, which may assist recognition by MutY/MUTYH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Pairing
  • DNA / chemistry
  • DNA Repair
  • Guanine* / chemistry
  • Humans
  • Nucleotides*

Substances

  • 8-hydroxyguanine
  • Nucleotides
  • Guanine
  • DNA