Mismatch repair-dependent mutagenesis in nondividing cells

Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6153-8. doi: 10.1073/pnas.1115361109. Epub 2012 Apr 2.

Abstract

Mismatch repair (MMR) is a major DNA repair pathway in cells from all branches of life that removes replication errors in a strand-specific manner, such that mismatched nucleotides are preferentially removed from the newly replicated strand of DNA. Here we demonstrate a role for MMR in helping create new phenotypes in nondividing cells. We show that mispairs in yeast that escape MMR during replication can later be subject to MMR activity in a replication strand-independent manner in nondividing cells, resulting in either fully wild-type or mutant DNA sequence. In one case, this activity is responsible for what appears to be adaptive mutation. This replication strand-independent MMR activity could contribute to the formation of tumors arising in nondividing cells and could also contribute to mutagenesis observed during somatic hypermutation of Ig genes.

Publication types

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

MeSH terms

  • Base Sequence
  • DNA Damage
  • DNA Mismatch Repair / genetics*
  • DNA Replication / genetics
  • DNA, Fungal / genetics
  • DNA, Fungal / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Genotype
  • Models, Genetic
  • Mutagenesis
  • Mutation*
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Tryptophan Synthase / genetics
  • Tryptophan Synthase / metabolism

Substances

  • DNA, Fungal
  • DNA-Binding Proteins
  • MSH6 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Tryptophan Synthase