title: Dynamic DNA binding licenses a repair factor to bypass roadblocks in search of DNA lesions.
abstract: 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.
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Maxwell W
authors.initials: MW
authors.lastname: Brown
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Yoori
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Williams
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Huck
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Surtees
authors.affiliation: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.|Center for Systems and Synthetic Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Ilya J
authors.initials: IJ
authors.lastname: Finkelstein
mesh_terms: D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D053843:DNA Mismatch Repair; D004260:DNA Repair; D004271:DNA, Fungal / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008856:Microscopy, Fluorescence; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D000074081:MutS Homolog 3 Protein; D009707:Nucleosomes / Q000378:metabolism; D045663:Quantum Dots; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D002843:Chromatin; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D006657:Histones; C081696:MSH3 protein, S cerevisiae; C098790:MSH6 protein, S cerevisiae; D000074081:MutS Homolog 3 Protein; D009707:Nucleosomes; D029701:Saccharomyces cerevisiae Proteins; C489751:MSH2 protein, S cerevisiae; D051718:MutS Homolog 2 Protein
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