Dynamic DNA binding licenses a repair factor to bypass roadblocks in search of DNA lesions

Nat Commun. 2016 Feb 3:7:10607. doi: 10.1038/ncomms10607.


DNA-binding proteins search for specific targets via facilitated diffusion along a crowded genome. However, little is known about how crowded DNA modulates facilitated diffusion and target recognition. Here we use DNA curtains and single-molecule fluorescence imaging to investigate how Msh2-Msh3, a eukaryotic mismatch repair complex, navigates on crowded DNA. Msh2-Msh3 hops over nucleosomes and other protein roadblocks, but maintains sufficient contact with DNA to recognize a single lesion. In contrast, Msh2-Msh6 slides without hopping and is largely blocked by protein roadblocks. Remarkably, the Msh3-specific mispair-binding domain (MBD) licences a chimeric Msh2-Msh6(3MBD) to bypass nucleosomes. Our studies contrast how Msh2-Msh3 and Msh2-Msh6 navigate on a crowded genome and suggest how Msh2-Msh3 locates DNA lesions outside of replication-coupled repair. These results also provide insights into how DNA repair factors search for DNA lesions in the context of chromatin.

Publication types

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

MeSH terms

  • Chromatin / metabolism
  • DNA Damage*
  • DNA Mismatch Repair*
  • DNA Repair
  • DNA, Fungal / metabolism*
  • DNA-Binding Proteins / metabolism*
  • Histones / metabolism
  • Microscopy, Fluorescence
  • MutS Homolog 2 Protein / metabolism*
  • MutS Homolog 3 Protein
  • Nucleosomes / metabolism
  • Quantum Dots
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins / metabolism*


  • Chromatin
  • DNA, Fungal
  • DNA-Binding Proteins
  • Histones
  • MSH3 protein, S cerevisiae
  • MSH6 protein, S cerevisiae
  • MutS Homolog 3 Protein
  • Nucleosomes
  • Saccharomyces cerevisiae Proteins
  • MSH2 protein, S cerevisiae
  • MutS Homolog 2 Protein