Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding

Area of Science:

• Molecular biology
• Genetics
• Cancer research

Background:

• DNA mismatch repair (MMR) corrects DNA replication errors, preventing cancer.
• Mutations in MMR genes, like MSH2, can cause cancer predisposition.
• Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare genetic disorder linked to MMR gene mutations.

Purpose of the Study:

• To investigate the functional impact of the V63E mutation in the MSH2 gene.
• To elucidate the molecular mechanism by which V63E affects MutSα protein function.
• To understand the basis of the mildly pathogenic phenotype observed in a patient with this mutation.

Main Methods:

• Characterization of the V63E mutant in mouse models.
• In vitro slippage and DNA repair assays.
• Cryogenic electron microscopy (cryo-EM) and surface plasmon resonance (SPR) analyses.

Main Results:

• The V63E mutation in MSH2 exhibits a mildly pathogenic phenotype.
• V63E disrupts a critical interface between the MSH2 and MSH6 mismatch binding domains (MBDs) within the MutSα complex.
• This disruption leads to reduced DNA binding affinity of MutSα.

Conclusions:

• The MSH2/MSH6 MBD interface acts as a 'safety lock' crucial for high-affinity DNA binding and replication fidelity.
• The V63E mutation impairs this safety lock, explaining the hypomorphic phenotype in patients.
• Understanding this mechanism aids in diagnosing and potentially treating CMMRD syndrome and related cancers.