Antimutator variants of DNA polymerases

Alan J. Herr, Lindsey N. Williams, Bradley D. Preston

Research output: Contribution to journalReview articlepeer-review

19 Scopus citations

Abstract

Evolution balances DNA replication speed and accuracy to optimize replicative fitness and genetic stability. There is no selective pressure to improve DNA replication fidelity beyond the background mutation rate from other sources, such as DNA damage. However, DNA polymerases remain amenable to amino acid substitutions that lower intrinsic error rates. Here, we review these 'antimutagenic' changes in DNA polymerases and discuss what they reveal about mechanisms of replication fidelity. Pioneering studies with bacteriophage T4 DNA polymerase (T4 Pol) established the paradigm that antimutator amino acid substitutions reduce replication errors by increasing proofreading efficiency at the expense of polymerase processivity. The discoveries of antimutator substitutions in proofreading-deficient 'mutator' derivatives of bacterial Pols I and III and yeast Pol δ suggest there must be additional antimutagenic mechanisms. Remarkably, many of the affected amino acid positions from Pol I, Pol III, and Pol δ are similar to the original T4 Pol substitutions. The locations of antimutator substitutions within DNA polymerase structures suggest that they may increase nucleotide selectivity and/or promote dissociation of primer termini from polymerases poised for misincorporation, leading to expulsion of incorrect nucleotides. If misincorporation occurs, enhanced primer dissociation from polymerase domains may improve proofreading in cis by an intrinsic exonuclease or in trans by alternate cellular proofreading activities. Together, these studies reveal that natural selection can readily restore replication error rates to sustainable levels following an adaptive mutator phenotype.

Original languageEnglish (US)
Pages (from-to)548-570
Number of pages23
JournalCritical Reviews in Biochemistry and Molecular Biology
Volume46
Issue number6
DOIs
StatePublished - Dec 2011
Externally publishedYes

Keywords

  • Cancer
  • DNA replication fidelity
  • Genetic adaptation
  • Genetic instability
  • Mutator
  • Protein structure/function

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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