ArticleNucleic acids research2023
Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding.
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, 1 of them a synthesis that pooled it.
What it found
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 10 citations in OpenAlex.
- ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management.European journal of human genetics : EJHG · 2024Guideline
- Nuclear PI3P produced by the Beclin-1/Vps34 complex regulates DNA mismatch repair.Nucleic acids research · 2026Article
- Article
- Elucidation of multiple high-resolution states of human MutSβ by cryo-EM reveals interplay between ATP/ADP binding and heteroduplex DNA recognition.Nucleic acids research · 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
- Constitutional mismatch repair deficiency mimicking Lynch syndrome is associated with hypomorphic mismatch repair gene variants.NPJ precision oncology · 2024Article
- Plant Organellar MSH1 Is a Displacement Loop-Specific Endonuclease.Plant & cell physiology · 2024Article
- New Discoveries on Protein Recruitment and Regulation during the Early Stages of the DNA Damage Response Pathways.International journal of molecular sciences · 2024Review
- 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
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
19 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair lead to a predisposition to cancer. Here, we study the homozygous mutation V63E in MSH2 that was found in the germline of a patient with suspected constitutional mismatch repair deficiency syndrome who developed colorectal cancer before the age of 30. Characterization of the mutant in mouse models, as well as slippage and repair assays, shows a mildly pathogenic phenotype. Using cryogenic electron microscopy and surface plasmon resonance, we explored the mechanistic effect of this mutation on MutSα function. We discovered that V63E disrupts a previously unappreciated interface between the mismatch binding domains (MBDs) of MSH2 and MSH6 and leads to reduced DNA binding. Our research identifies this interface as a 'safety lock' that ensures high-affinity DNA binding to increase replication fidelity. Our mechanistic model explains the hypomorphic phenotype of the V63E patient mutation and other variants in the MBD interface.
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Registered trials
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.