Structural basis for removal of adenine mispaired with 8-oxoguanine by MutY adenine DNA glycosylase

Nature. 2004 Feb 12;427(6975):652-6. doi: 10.1038/nature02306.

Abstract

The genomes of aerobic organisms suffer chronic oxidation of guanine to the genotoxic product 8-oxoguanine (oxoG). Replicative DNA polymerases misread oxoG residues and insert adenine instead of cytosine opposite the oxidized base. Both bases in the resulting A*oxoG mispair are mutagenic lesions, and both must undergo base-specific replacement to restore the original C*G pair. Doing so represents a formidable challenge to the DNA repair machinery, because adenine makes up roughly 25% of the bases in most genomes. The evolutionarily conserved enzyme adenine DNA glycosylase (called MutY in bacteria and hMYH in humans) initiates repair of A*oxoG to C*G by removing the inappropriately paired adenine base from the DNA backbone. A central issue concerning MutY function is the mechanism by which A*oxoG mispairs are targeted among the vast excess of A*T pairs. Here we report the use of disulphide crosslinking to obtain high-resolution crystal structures of MutY-DNA lesion-recognition complexes. These structures reveal the basis for recognizing both lesions in the A*oxoG pair and for catalysing removal of the adenine base.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine / metabolism*
  • Base Pairing
  • Binding Sites
  • Catalysis
  • Cross-Linking Reagents
  • Crystallography, X-Ray
  • DNA / chemistry
  • DNA / metabolism*
  • DNA Glycosylases / chemistry*
  • DNA Glycosylases / metabolism*
  • Disulfides / metabolism
  • Geobacillus stearothermophilus / enzymology*
  • Geobacillus stearothermophilus / genetics
  • Guanine / analogs & derivatives*
  • Guanine / metabolism*
  • Models, Molecular
  • N-Glycosyl Hydrolases / chemistry*
  • N-Glycosyl Hydrolases / metabolism
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • Cross-Linking Reagents
  • Disulfides
  • 8-hydroxyguanine
  • Guanine
  • DNA
  • DNA Glycosylases
  • N-Glycosyl Hydrolases
  • adenine glycosylase
  • mutY adenine glycosylase
  • Adenine

Associated data

  • PDB/1RRQ
  • PDB/1RRS
  • PDB/1RRT