Abstract
Mismatch recognition by the human MutS homologs hMSH2-hMSH6 is regulated by adenosine nucleotide binding, supporting the hypothesis that it functions as a molecular switch. Here we show that ATP-induced release of hMSH2-hMSH6 from mismatched DNA is prevented if the ends are blocked or if the DNA is circular. We demonstrate that mismmatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts hMSH2-hMSH6 into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. Our results support a model for bidirectional mismatch repair in which stochastic loading of multiple ATP-bound hMSH2-hMSH6 sliding clamps onto mismatch-containing DNA leads to activation of the repair machinery and/or other signaling effectors similar to G protein switches.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphatases*
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Adenosine Triphosphate / physiology
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Bacterial Proteins / physiology
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Base Pairing
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DNA Damage*
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DNA Repair*
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DNA-Binding Proteins*
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Diffusion
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Escherichia coli Proteins*
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Fungal Proteins / physiology*
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Humans
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Hydrolysis
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Magnesium / physiology
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Models, Genetic
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MutL Proteins
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MutS DNA Mismatch-Binding Protein
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MutS Homolog 2 Protein
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Protein Conformation
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Proto-Oncogene Proteins / physiology*
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Saccharomyces cerevisiae Proteins*
Substances
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Bacterial Proteins
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DNA-Binding Proteins
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Escherichia coli Proteins
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Fungal Proteins
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MSH6 protein, S cerevisiae
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MutL protein, E coli
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Proto-Oncogene Proteins
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Saccharomyces cerevisiae Proteins
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Adenosine Triphosphate
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Adenosine Triphosphatases
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MSH2 protein, human
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MutL Proteins
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MutS DNA Mismatch-Binding Protein
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MutS Homolog 2 Protein
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MutS protein, E coli
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Magnesium