ArticleNucleic acids research2023
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.
Article in Nucleic acids research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 7 citations in OpenAlex.
- Redundant mispair excision mechanisms in eukaryotic DNA mismatch repair.Nucleus (Austin, Tex.) · 2026Review
- Analysis of structure and conservation for supporting functional evaluation of PMS2 missense variants.European journal of human genetics : EJHG · 2026Article
- Exome Sequencing Identifies Variants in MLH1 and ERBB2 as Potential Cancer-Predisposing Factors in Familial Early-Onset Colorectal Cancer.The Kaohsiung journal of medical sciences · 2026Article
- The marsupial imprinted gene MLH1 has retrocopies in three marsupial families.Epigenetics & chromatin · 2026Article
- Disruption of protein-protein interaction hotspots in the C-terminal domain of MLH1 confers mismatch repair deficiency.NAR cancer · 2025Article
- Microsatellite instability and PD-L1 expression in sarcomas: current evidence and clinical perspectives.Medical oncology (Northwood, London, England) · 2025Review
- Combining single-molecule and structural studies reveals protein and DNA conformations and assemblies that govern DNA mismatch repair.Current opinion in structural biology · 2024Review
- Article
- Molecular basis of the phenotypic variants arising from aMicrobial genomics · 2023Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
DNA mismatch repair (MMR) is essential for correction of DNA replication errors. Germline mutations of the human MMR gene MLH1 are the major cause of Lynch syndrome, a heritable cancer predisposition. In the MLH1 protein, a non-conserved, intrinsically disordered region connects two conserved, catalytically active structured domains of MLH1. This region has as yet been regarded as a flexible spacer, and missense alterations in this region have been considered non-pathogenic. However, we have identified and investigated a small motif (ConMot) in this linker which is conserved in eukaryotes. Deletion of the ConMot or scrambling of the motif abolished mismatch repair activity. A mutation from a cancer family within the motif (p.Arg385Pro) also inactivated MMR, suggesting that ConMot alterations can be causative for Lynch syndrome. Intriguingly, the mismatch repair defect of the ConMot variants could be restored by addition of a ConMot peptide containing the deleted sequence. This is the first instance of a DNA mismatch repair defect conferred by a mutation that can be overcome by addition of a small molecule. Based on the experimental data and AlphaFold2 predictions, we suggest that the ConMot may bind close to the C-terminal MLH1-PMS2 endonuclease and modulate its activation during the MMR process.
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