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Mol Cell Biol, March 1998, p. 1635-1641, Vol. 18, No. 3
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

A Naturally Occurring hPMS2 Mutation Can Confer a Dominant Negative Mutator Phenotype

Nicholas C. Nicolaides,1,2,* Susan J. Littman,3 Paul Modrich,3,4 Kenneth W. Kinzler,1 and Bert Vogelstein1,5

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

Received 8 August 1997/Returned for modification 22 September 1997/Accepted 26 November 1997

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.

* Corresponding author. Mailing address: Magainin Pharmaceuticals, Inc., Magainin Institute of Molecular Medicine, 5110 Campus Dr., Plymouth Meeting, PA 19462. Phone: (610) 941-5283. Fax: (610) 941-5399. E-mail: nnicolaides.{at}magainin.com.




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