ArticlePLoS genetics2013
Dominant mutations in S. cerevisiae PMS1 identify the Mlh1-Pms1 endonuclease active site and an exonuclease 1-independent mismatch repair pathway.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 63 citations in OpenAlex.
- Redundant mispair excision mechanisms in eukaryotic DNA mismatch repair.Nucleus (Austin, Tex.) · 2026Review
- DNA mismatch repair mediated by Mlh1-Pms1 endonuclease-catalyzed mispair excision.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Disentangling the mutational effects on protein stability and interaction of human MLH1.PLoS genetics · 2025Article
- Mlh1-Pms1 ATPase activity is regulated distinctly by self-generated nicks and strand discrimination signals in mismatch repair.Nucleic acids research · 2025Article
- Functions of PMS2 and MLH1 important for regulation of divergent repeat-mediated deletions.DNA repair · 2025Article
- Combining single-molecule and structural studies reveals protein and DNA conformations and assemblies that govern DNA mismatch repair.Current opinion in structural biology · 2024Review
- Instability throughout the Saccharomyces cerevisiae genome resulting from Pms1 endonuclease deficiency.Nucleic acids research · 2024Article
- Functions of PMS2 and MLH1 important for regulation of divergent repeat-mediated deletions.bioRxiv : the preprint server for biology · 2024Article
- The Mlh1-Pms1 endonuclease uses ATP to preserve DNA discontinuities as strand discrimination signals to facilitate mismatch repair.bioRxiv : the preprint server for biology · 2024Article
- Article
- Elevated MSH2 MSH3 expression interferes with DNA metabolism in vivo.Nucleic acids research · 2023Article
- Insights into DNA cleavage by MutL homologs from analysis of conserved motifs in eukaryotic Mlh1.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023Article
- A conserved motif in the disordered linker of human MLH1 is vital for DNA mismatch repair and its function is diminished by a cancer family mutation.Nucleic acids research · 2023Article
- Resolution of sequence divergence for repeat-mediated deletions shows a polarity that is mediated by MLH1.Nucleic acids research · 2023Article
- Investigation of germline variants in Bahraini women with breast cancer using next-generation sequencing based-multigene panel.PloS one · 2023Article
- Article
- The unstructured linker of Mlh1 contains a motif required for endonuclease function which is mutated in cancers.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Biosensor-CoupledmSystems · 2022Article
- Inhibition of ABL1 by tyrosine kinase inhibitors leads to a downregulation of MLH1 by Hsp70-mediated lysosomal protein degradation.Frontiers in genetics · 2022Article
- Functional characterization of MLH1 missense variants unveils mechanisms of pathogenicity and clarifies role in cancer.PloS one · 2022Article
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8 authors at 1 institution in 1 country.
Funding
Abstract
Lynch syndrome (hereditary nonpolypsis colorectal cancer or HNPCC) is a common cancer predisposition syndrome. Predisposition to cancer in this syndrome results from increased accumulation of mutations due to defective mismatch repair (MMR) caused by a mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2/scPMS1. To better understand the function of Mlh1-Pms1 in MMR, we used Saccharomyces cerevisiae to identify six pms1 mutations (pms1-G683E, pms1-C817R, pms1-C848S, pms1-H850R, pms1-H703A and pms1-E707A) that were weakly dominant in wild-type cells, which surprisingly caused a strong MMR defect when present on low copy plasmids in an exo1Δ mutant. Molecular modeling showed these mutations caused amino acid substitutions in the metal coordination pocket of the Pms1 endonuclease active site and biochemical studies showed that they inactivated the endonuclease activity. This model of Mlh1-Pms1 suggested that the Mlh1-FERC motif contributes to the endonuclease active site. Consistent with this, the mlh1-E767stp mutation caused both MMR and endonuclease defects similar to those caused by the dominant pms1 mutations whereas mutations affecting the predicted metal coordinating residue Mlh1-C769 had no effect. These studies establish that the Mlh1-Pms1 endonuclease is required for MMR in a previously uncharacterized Exo1-independent MMR pathway.
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