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

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.

ACKNOWLEDGMENTS

We thank Luigi Grasso for his technical assistance.

This work was supported by National Cancer Institute grants CA35494, CA62924 (to B.V.), and CA71544 (to S.J.L.) and by NIGMS grant GM45190 (to P.M.). B.V. and P.M. are Investigators of the Howard Hughes Medical Institute.

ADDENDUM IN PROOF

Another hPMS2 mutation giving rise to an apparent dominant form of microsatellite instability has recently been described (Oncogene 15:2877–2881, 1997).