ArticleNucleic acids research2006
Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair.
Article in Nucleic acids research, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 74 citations in OpenAlex.
- Mismatch repair protein MLH1 controls testis development by regulating the Hippo-YAP signaling pathway.Nucleic acids research · 2026Article
- Analysis of structure and conservation for supporting functional evaluation of PMS2 missense variants.European journal of human genetics : EJHG · 2026Article
- The Tyrolean FounderBiomolecules · 2026Article
- The GHKL ATPase Family as a Paradigm for MutL Homolog Function in DNA Mismatch Repair.International journal of molecular sciences · 2025Review
- Physiological and molecular responses of Pyropia yezoensis thallus to high-light stress.BMC plant biology · 2025Article
- Identification and in silico evaluation of natural compounds from Annona muricata (soursop) leaves for colon cancer treatment.Scientific reports · 2025Article
- The landscape of germline variants in breast and colorectal cancer susceptibility genes in patients with pituitary tumours.Journal of neuro-oncology · 2025Article
- Therapeutic targeting of mismatch repair-deficient cancers.Nature reviews. Clinical oncology · 2025Review
- Advances in diagnostic and therapeutic applications of mismatch repair loss in cancer.DNA repair · 2025Review
- New Discoveries on Protein Recruitment and Regulation during the Early Stages of the DNA Damage Response Pathways.International journal of molecular sciences · 2024Review
- Article
- Elevated MSH2 MSH3 expression interferes with DNA metabolism in vivo.Nucleic acids research · 2023Article
- Key role of phosphorylation sites in ATPase domain and Linker region of MLH1 for DNA binding and functionality of MutLα.Scientific reports · 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
- Genetic mutations in HER2-positive breast cancer: possible association with response to trastuzumab therapy.Human genomics · 2023Article
- A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants.Human mutation · 2022Article
- Article
- Functional characterization of MLH1 missense variants unveils mechanisms of pathogenicity and clarifies role in cancer.PloS one · 2022Article
- Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability.Critical reviews in biochemistry and molecular biology · 2021Review
- Identification of MLH2/hPMS1 dominant mutations that prevent DNA mismatch repair function.Communications biology · 2020Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
MutLalpha, a heterodimer of MLH1 and PMS2, plays a central role in human DNA mismatch repair. It interacts ATP-dependently with the mismatch detector MutSalpha and assembles and controls further repair enzymes. We tested if the interaction of MutLalpha with DNA-bound MutSalpha is impaired by cancer-associated mutations in MLH1, and identified one mutation (Ala128Pro) which abolished interaction as well as mismatch repair activity. Further examinations revealed three more residues whose mutation interfered with interaction. Homology modelling of MLH1 showed that all residues clustered in a small accessible surface patch, suggesting that the major interaction interface of MutLalpha for MutSalpha is located on the edge of an extensive beta-sheet that backs the MLH1 ATP binding pocket. Bioinformatic analysis confirmed that this patch corresponds to a conserved potential protein-protein interaction interface which is present in both human MLH1 and its E.coli homologue MutL. MutL could be site-specifically crosslinked to MutS from this patch, confirming that the bacterial MutL-MutS complex is established by the corresponding interface in MutL. This is the first study that identifies the conserved major MutLalpha-MutSalpha interaction interface in MLH1 and demonstrates that mutations in this interface can affect interaction and mismatch repair, and thereby can also contribute to cancer development.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.