A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype.
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.
Nicolaides
N C
NC
Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA. nnicolaides.@magainin.com
Littman
S J
SJ
Modrich
P
P
Kinzler
K W
KW
Vogelstein
B
B
D000251:Adenosine Triphosphatases; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000378:metabolism; D029968:Escherichia coli Proteins; D006367:HeLa Cells; D006801:Humans; D008647:Mesocricetus; D000070976:Mismatch Repair Endonuclease PMS2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000070956:MutL Proteins; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009692:Nucleic Acid Heteroduplexes; D010641:Phenotype
D000251:Adenosine Triphosphatases; D001426:Bacterial Proteins; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D000070976:Mismatch Repair Endonuclease PMS2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000070956:MutL Proteins; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins; D009692:Nucleic Acid Heteroduplexes; C078444:MSH3 protein, human; C074770:MutL protein, E coli; C094934:PMS2 protein, human; C421109:multidrug resistance-associated protein 1