ArticleMolecular and cellular biology2001
Inactivation of DNA mismatch repair by increased expression of yeast MLH1.
Article in Molecular and cellular biology, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 53 citations in OpenAlex.
- Bacillus subtilis MutL samples multiple conformations during nucleotide binding and hydrolysis.Structure (London, England : 1993) · 2026Article
- The ubiquitin ligase UBR4 and the deubiquitylase USP5 modulate the stability of DNA mismatch repair protein MLH1.The Journal of biological chemistry · 2024Article
- MRE11A: a novel negative regulator of human DNA mismatch repair.Cellular & molecular biology letters · 2024Article
- Elevated MSH2 MSH3 expression interferes with DNA metabolism in vivo.Nucleic acids research · 2023Article
- Multiplexed Guide RNA Expression Leads to Increased Mutation Frequency in Targeted Window Using a CRISPR-Guided Error-Prone DNA Polymerase inACS synthetic biology · 2023Article
- Translesion DNA synthesis-driven mutagenesis in very early embryogenesis of fast cleaving embryos.Nucleic acids research · 2022Article
- MutSα mismatch repair protein stability is governed by subunit interaction, acetylation, and ubiquitination.G3 (Bethesda, Md.) · 2021Article
- Review
- Genetic evidence for the involvement of mismatch repair proteins, PMS2 and MLH3, in a late step of homologous recombination.The Journal of biological chemistry · 2020Article
- MSH2 Overexpression Due to an Unclassified Variant in 3'-Untranslated Region in a Patient with Colon Cancer.Biomedicines · 2020Article
- Genomic Instability Promoted by Overexpression of Mismatch Repair Factors in Yeast: A Model for Understanding Cancer Progression.Genetics · 2018Article
- Overexpression of MutL homolog 1 and MutS homolog 2 proteins have reversed prognostic implications for stage I-II colon cancer patients.Biomedical journal · 2017Article
- Novel Implications in Molecular Diagnosis of Lynch Syndrome.Gastroenterology research and practice · 2017Review
- New insights into the mechanism of DNA mismatch repair.Chromosoma · 2015Review
- Single molecule studies of DNA mismatch repair.DNA repair · 2014Review
- Yeast mutator phenotype enforced by Arabidopsis PMS1 expression.Molecular biology reports · 2013Article
- Mismatch repair hMSH2, hMLH1, hMSH6 and hPMS2 mRNA expression profiles in precancerous and cancerous urothelium.Oncology letters · 2013Article
- Modulation of microRNA processing by mismatch repair protein MutLα.Cell research · 2012Article
- Over-Expression of YLR162W in Saccharomyces cerevisiae Inhibits Cell Proliferation and Renders Cells Susceptible to the Hypoxic Conditions Induced by Cobalt Chloride.Indian journal of microbiology · 2011Article
- PMS1 from Arabidopsis thaliana: optimization of protein overexpression in Escherichia coli.Molecular biology reports · 2011Article
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
Inactivation of DNA mismatch repair by mutation or by transcriptional silencing of the MLH1 gene results in genome instability and cancer predisposition. We recently found (P. V. Shcherbakova and T. A. Kunkel, Mol. Cell. Biol. 19:3177-3183, 1999) that an elevated spontaneous mutation rate can also result from increased expression of yeast MLH1. Here we investigate the mechanism of this mutator effect. Hybridization of poly(A)(+) mRNA to DNA microarrays containing 96.4% of yeast open reading frames revealed that MLH1 overexpression did not induce changes in expression of other genes involved in DNA replication or repair. MLH1 overexpression strongly enhanced spontaneous mutagenesis in yeast strains with defects in the 3'-->5' exonuclease activity of replicative DNA polymerases delta and epsilon but did not enhance the mutation rate in strains with deletions of MSH2, MLH1, or PMS1. This suggests that overexpression of MLH1 inactivates mismatch repair of replication errors. Overexpression of the PMS1 gene alone caused a moderate increase in the mutation rate and strongly suppressed the mutator effect caused by MLH1 overexpression. The mutator effect was also reduced by a missense mutation in the MLH1 gene that disrupted Mlh1p-Pms1p interaction. Analytical ultracentrifugation experiments showed that purified Mlh1p forms a homodimer in solution, albeit with a K(d) of 3.14 microM, 36-fold higher than that for Mlh1p-Pms1p heterodimerization. These observations suggest that the mismatch repair defect in cells overexpressing MLH1 results from an imbalance in the levels of Mlh1p and Pms1p and that this imbalance might lead to formation of nonfunctional mismatch repair complexes containing Mlh1p homodimers.
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