Identification and characterization of a novel mechanism resulting in DNA Mismatch repair defects
Human Genetics
Cell Biology
Final Report Abstract
Every living organism has to make copies of the genetic information before cells can divide. The process of making copies of the genetic information (DNA) is also called DNA replication and constitutes a constant challenge for the integrity of the cell. Changes in the genetic information (also called mutations) can lead to cell death or diseases like cancer. For this reason, living organisms possess a variety of quality control mechanisms that guarantee the faithful duplication of the genetic information. One of these mechanisms is the Mismatch repair (MMR) pathway that identifies and correct mutations that arise on the newly replicated DNA. Previous studies have shown that inactivation of the MMR pathway is associated with the accumulation of mutations and increased cancer predisposition. In this study, we identified in budding yeast a group of mutations in an MMR-related gene called MLH2 that resulted in a mutator phenotype. Importantly, previous studies have shown that ablation of this gene does not cause a mutator phenotype. Here, in a random mutagenesis screen we identified a group of missense mlh2 mutations that interfere with MMR function in a dominant manner. By using a variety of cellular and molecular approaches, we showed that specific mlh2 mutations resulted in mutant complexes that remain attached on DNA, where they prevent the corrective function of MMR proteins. We could also show that homolog mutations in other MMR genes have similar negative consequences on MMR function in yeast but also in human cells. Thus, we identified and characterized a novel mechanism that can explain a mutator phenotype in the absence of mutations on key MMR components. Moreover, our work predicts that homolog mutations in other MMR-related genes may inactivate MMR function in a dominant manner, which might be more deleterious than mutations resulting in truncated or unstable proteins. Patients carrying this type of mutations may benefit of familial genetic counseling and regular screenings for early cancer detection.
Publications
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Identification of MLH2/hPMS1 dominant mutations that prevent DNA mismatch repair function. Communications Biology. 2020 Dec 10;3(1):751
Reyes GX, Zhao B, Schmidt TT, Gries K, Kloor M, Hombauer H
