Structural basis for error-free replication of oxidatively damaged DNA by yeast DNA polymerase η

Structure. 2010 Nov 10;18(11):1463-70. doi: 10.1016/j.str.2010.08.019.

Abstract

7,8-dihydro-8-oxoguanine (8-oxoG) adducts are formed frequently by the attack of oxygen-free radicals on DNA. They are among the most mutagenic lesions in cells because of their dual coding potential, where, in addition to normal base-pairing of 8-oxoG(anti) with dCTP, 8-oxoG in the syn conformation can base pair with dATP, causing G to T transversions. We provide here for the first time a structural basis for the error-free replication of 8-oxoG lesions by yeast DNA polymerase η (Polη). We show that the open active site cleft of Polη can accommodate an 8-oxoG lesion in the anti conformation with only minimal changes to the polymerase and the bound DNA: at both the insertion and post-insertion steps of lesion bypass. Importantly, the active site geometry remains the same as in the undamaged complex and provides a basis for the ability of Polη to prevent the mutagenic replication of 8-oxoG lesions in cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Catalytic Domain / genetics
  • Crystallography
  • DNA Adducts / chemistry
  • DNA Adducts / genetics
  • DNA Repair*
  • DNA Replication / physiology*
  • DNA-Directed DNA Polymerase / chemistry*
  • DNA-Directed DNA Polymerase / metabolism*
  • Guanine / analogs & derivatives
  • Guanine / chemistry
  • Models, Molecular*
  • Protein Conformation*
  • Saccharomyces cerevisiae / enzymology*

Substances

  • 7,8-dihydro-8-oxoguanine
  • DNA Adducts
  • Guanine
  • DNA-Directed DNA Polymerase
  • Rad30 protein