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Visualization of eukaryotic DNA mismatch repair reveals distinct recognition and repair intermediates.

DNA mismatch repair (MMR) increases replication fidelity by eliminating mispaired bases resulting from replication errors. In Saccharomyces cerevisiae, mispairs are primarily detected by the Msh2-Msh6 complex and corrected following recruitment of the Mlh1-Pms1 complex. Here, we visualized functional fluorescent versions of Msh2-Msh6 and Mlh1-Pms1 in living cells. We found that the Msh2-Msh6 complex is an S phase component of replication centers independent of mispaired bases; this localized pool accounted for 10%-15% of MMR in wild-type cells but was essential for MMR in the absence of Exo1. Unexpectedly, Mlh1-Pms1 formed nuclear foci that, although dependent on Msh2-Msh6 for formation, rarely colocalized with Msh2-Msh6 replication-associated foci. Mlh1-Pms1 foci increased when the number of mispaired bases was increased; in contrast, Msh2-Msh6 foci were unaffected. These findings suggest the presence of replication machinery-coupled and -independent pathways for mispair recognition by Msh2-Msh6, which direct formation of superstoichiometric Mlh1-Pms1 foci that represent sites of active MMR.

Pubmed ID: 22118461

Authors

  • Hombauer H
  • Campbell CS
  • Smith CE
  • Desai A
  • Kolodner RD

Journal

Cell

Publication Data

November 23, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: CA23100
  • Agency: NIGMS NIH HHS, Id: GM074215
  • Agency: NIGMS NIH HHS, Id: GM085764
  • Agency: NIGMS NIH HHS, Id: GM50006
  • Agency: NCI NIH HHS, Id: P30 CA023100
  • Agency: NCI NIH HHS, Id: P30 CA023100-27
  • Agency: NIGMS NIH HHS, Id: P50 GM085764
  • Agency: NIGMS NIH HHS, Id: R01 GM050006
  • Agency: NIGMS NIH HHS, Id: R01 GM050006-24
  • Agency: NIGMS NIH HHS, Id: R01 GM074215
  • Agency: NIGMS NIH HHS, Id: R01 GM074215-08

Mesh Terms

  • Animals
  • DNA Mismatch Repair
  • DNA Repair Enzymes
  • DNA Replication
  • DNA-Binding Proteins
  • Exodeoxyribonucleases
  • Humans
  • MutS Homolog 2 Protein
  • Proliferating Cell Nuclear Antigen
  • Saccharomyces cerevisiae