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A Naturally Occurring hPMS2 Mutation Can Confer a Dominant Negative Mutator Phenotype |
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| Authors: | Nicholas C. Nicolaides Susan J. Littman Paul Modrich Kenneth W. Kinzler Bert Vogelstein |
| Affiliation: | Johns Hopkins Oncology Center1. and Howard Hughes Medical Institute,5. Baltimore, Maryland 21231; Magainin Institute of Molecular Medicine, Magainin Pharmaceuticals, Inc., Plymouth Meeting, Pennsylvania 194622.; and Department of Medicine and Oncology, Duke University Medical Center,3. and Department of Biochemistry and Howard Hughes Medical Institute, Duke University,4. Durham, North Carolina 27710 |
| 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. |
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