Abstract
Defects in mismatch repair (MMR) genes result in a mutator phenotype by inducing microsatellite instability (MI), a characteristic of hereditary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the mechanism by which germ line mutations in MMR genes predispose kindreds to HNPCC suggest a "two-hit" inactivation of both alleles of a particular MMR gene. Here we present experimental evidence that a nonsense mutation at codon 134 of the hPMS2 gene is sufficient to reduce MMR and induce MI in cells containing a wild-type hPMS2 allele. These results have significant implications for understanding the relationship between mutagenesis and carcinogenesis and the ability to generate mammalian cells with mutator phenotypes.
Publication types
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Research Support, Non-U.S. Gov't
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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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Animals
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Bacterial Proteins / metabolism
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Cell Line
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Cricetinae
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DNA Repair Enzymes*
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DNA Repair*
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DNA-Binding Proteins / metabolism
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Escherichia coli Proteins*
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HeLa Cells
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Humans
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Mesocricetus
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Mismatch Repair Endonuclease PMS2
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Multidrug Resistance-Associated Proteins*
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MutL Proteins
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MutS Homolog 3 Protein
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Mutation*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Nucleic Acid Heteroduplexes
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Phenotype
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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MSH3 protein, human
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Multidrug Resistance-Associated Proteins
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MutL protein, E coli
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MutS Homolog 3 Protein
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Neoplasm Proteins
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Nucleic Acid Heteroduplexes
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Adenosine Triphosphatases
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PMS2 protein, human
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Mismatch Repair Endonuclease PMS2
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MutL Proteins
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DNA Repair Enzymes
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multidrug resistance-associated protein 1