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Published on: February 8, 2010
PMS2 expression decrease causes severe problems in mismatch repair
Mariann Kasela1, Minna Nyström1, Minttu Kansikas1
1Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
Abstract:
PMS2 is one of the four susceptibility genes in Lynch syndrome (LS), the most common cancer syndrome in the world. Inherited mutations in DNA mismatch repair (MMR) genes, MLH1, MSH2, and MSH6, account for approximately 90% of LS, while a relatively small number of LS families segregate a PMS2 mutation. This and the low cancer penetrance in PMS2 families suggest that PMS2 is only a moderate or low-risk susceptibility gene. We have previously shown that even a partial expression decrease in MLH1, MSH2, or MSH6 suggests that heterozygous LS mutation carriers have MMR malfunction in constitutive tissues. Whether and how PMS2 expression decrease affects the repair capability is not known. Here, we show that PMS2 knockdown cells retaining 19%, 33%, or 53% of PMS2 expression all have significantly reduced MMR efficiency. Surprisingly, the cells retaining expression levels comparable to PMS2 mutation carriers indicate the lowest repair efficiency.
Insights
Reduced PMS2 gene expression impairs DNA mismatch repair efficiency, even at levels found in Lynch syndrome mutation carriers. This finding clarifies PMS2's role in DNA repair and cancer risk.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Lynch syndrome (LS) is the most common hereditary cancer syndrome.
- PMS2 is a susceptibility gene for LS, but its role is less understood than MLH1, MSH2, and MSH6.
- Previous studies show reduced expression of other LS genes impairs DNA repair.
Purpose of the Study:
- To investigate the impact of reduced PMS2 expression on DNA mismatch repair (MMR) efficiency.
- To determine if decreased PMS2 levels in cells correlate with MMR malfunction.
Main Methods:
- Utilized PMS2 knockdown cell models with varying residual PMS2 expression levels (19%, 33%, 53%).
- Assessed DNA mismatch repair efficiency in these modified cells.
Main Results:
- All tested levels of PMS2 knockdown significantly reduced MMR efficiency.
- Cells with PMS2 expression levels similar to those in LS mutation carriers exhibited the lowest repair efficiency.
Conclusions:
- Decreased PMS2 expression demonstrably impairs DNA mismatch repair capability.
- PMS2 is a critical gene for maintaining MMR function, even at moderate expression levels, impacting Lynch syndrome risk assessment.
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