Structures of mismatch replication errors observed in a DNA polymerase

Cell. 2004 Mar 19;116(6):803-16. doi: 10.1016/s0092-8674(04)00252-1.


Accurate DNA replication is essential for genomic stability. One mechanism by which high-fidelity DNA polymerases maintain replication accuracy involves stalling of the polymerase in response to covalent incorporation of mismatched base pairs, thereby favoring subsequent mismatch excision. Some polymerases retain a "short-term memory" of replication errors, responding to mismatches up to four base pairs in from the primer terminus. Here we a present a structural characterization of all 12 possible mismatches captured at the growing primer terminus in the active site of a polymerase. Our observations suggest four mechanisms that lead to mismatch-induced stalling of the polymerase. Furthermore, we have observed the effects of extending a mismatch up to six base pairs from the primer terminus and find that long-range distortions in the DNA transmit the presence of the mismatch back to the enzyme active site, suggesting the structural basis for the short-term memory of replication errors.

Publication types

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

MeSH terms

  • Base Pair Mismatch / genetics*
  • Base Sequence / genetics
  • DNA / biosynthesis*
  • DNA / genetics*
  • DNA Replication / genetics*
  • DNA-Directed DNA Polymerase / genetics*
  • DNA-Directed DNA Polymerase / metabolism
  • Geobacillus stearothermophilus
  • Models, Molecular
  • Mutation / genetics
  • Nucleotides / genetics
  • Protein Structure, Tertiary / genetics
  • Purines / chemistry
  • Pyrimidines / chemistry


  • Nucleotides
  • Purines
  • Pyrimidines
  • DNA
  • DNA-Directed DNA Polymerase