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A naturally occurring hPMS2 mutation can confer a dominant negative mutator phenotype
N C Nicolaides1, S J Littman, P Modrich
1Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA. nnicolaides.@magainin.com
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.
Insights
Defects in mismatch repair (MMR) genes can lead to cancer. A single mutation in the hPMS2 gene was found to be sufficient to cause microsatellite instability, a hallmark of certain cancers.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Defects in DNA mismatch repair (MMR) genes cause a mutator phenotype, leading to microsatellite instability (MI).
- MI is a characteristic of hereditary nonpolyposis colorectal cancer (HNPCC) and some sporadic colon tumors.
- Current models propose a "two-hit" mechanism involving inactivation of both alleles of an MMR gene for HNPCC predisposition.
Purpose of the Study:
- To investigate if a single mutation in the hPMS2 gene can induce MMR deficiency and MI.
- To challenge the existing "two-hit" hypothesis for MMR gene inactivation in cancer predisposition.
Main Methods:
- The study focused on a nonsense mutation at codon 134 of the human PMS2 (hPMS2) gene.
- Experimental analysis was conducted on cells with both a mutated and a wild-type hPMS2 allele.
Main Results:
- A nonsense mutation at codon 134 of hPMS2 was demonstrated to be sufficient to reduce MMR efficiency.
- This single mutation was also shown to induce microsatellite instability (MI) in cells with a wild-type hPMS2 allele.
- These findings indicate that a single mutated allele can impact MMR function.
Conclusions:
- A single nonsense mutation in the hPMS2 gene can lead to MMR deficiency and microsatellite instability.
- This challenges the traditional "two-hit" model, suggesting a single hit may be sufficient in certain contexts.
- The results have implications for understanding mutagenesis, carcinogenesis, and generating mammalian cells with mutator phenotypes.