A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype

Nicholas C. Nicolaides, Susan J. Littman, Paul Modrich, Kenneth W. Kinzler, Bert Vogelstein

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1635-1641
Number of pages7
JournalMolecular and cellular biology
Volume18
Issue number3
DOIs
StatePublished - Mar 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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