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Updated: Feb 7, 2026
Imaging Mismatch Repair and Cellular Responses to DNA Damage in Bacillus subtilis
Published on: February 8, 2010
Mismatch repair MLH complexes make distinct contributions to post-replicative mismatch repair versus trinucleotide
Katherine M Casazza1, Greg M Williams1,2, Lauren Johengen1
1Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14203.
Abstract:
Mismatch repair (MMR) is a highly conserved DNA repair pathway that promotes genome stability by directing the repair of errors in DNA replication. In Saccharomyces cerevisiae, MMR is initiated by either Msh2-Msh3 or Msh2-Msh6, via recognition of insertion deletion loops (IDLs; up to ~ 17 nucleotides) and misincorporation events, respectively. Both complexes recognize and bind small (1-2 nucleotide) IDLs. Once bound, MSH complexes recruit one or more downstream MLH complexes to continue repair: Mlh1-Pms1, Mlh1-Mlh2 and/or Mlh1-Mlh3. Msh2-Msh3 also promotes CAG trinucleotide repeat (TNR) expansions through specific DNAbinding to TNR DNA structures, followed by recruitment of MLH complexes. These expansions lead to genome instability that causes neurodegenerative diseases such as Huntington's Disease in humans. Here, we defined a hierarchy of MLH function in these Msh2-Msh3mediated pathways in vivo in S. cerevisiae. We determined that Mlh1-Pms1 is the primary MLH complex required in Msh2-Msh3-mediated MMR. In contrast, all three MLH complexes were required to promote CAG expansions, with loss of Mlh1-Pms1 or Mlh1-Mlh2 exhibiting the strongest effects. Mutations in PMS1 and MLH3 were synergistic. We propose a model in which Mlh1-Pms1 is primarily responsible for "appropriate" Msh2-Msh3-mediated MMR, while all three MLH complexes collaborate specifically in the presence of CAG structure, to promote a "pathogenic" Msh2-Msh3-mediated pathway that leads to expansions. Our model highlights the importance of DNA structure-dependent conformations in modulating MLH function.
Insights
Mismatch repair (MMR) pathways in yeast use MSH complexes to fix DNA errors. Different MLH complexes have distinct roles in standard MMR versus CAG repeat expansions linked to disease.
Area of Science:
- Molecular Biology
- Genetics
- DNA Repair Mechanisms
Background:
- Mismatch repair (MMR) is crucial for maintaining genome stability by correcting DNA replication errors.
- In yeast, MSH complexes (Msh2-Msh3, Msh2-Msh6) initiate MMR by recognizing DNA lesions like insertion-deletion loops (IDLs).
- Msh2-Msh3 also mediates CAG trinucleotide repeat (TNR) expansions, implicated in human neurodegenerative diseases.
Purpose of the Study:
- To elucidate the hierarchical function of downstream MLH complexes in Msh2-Msh3-mediated MMR and CAG repeat expansions in yeast.
- To differentiate the roles of MLH complexes in canonical MMR versus structure-dependent TNR expansion pathways.
Main Methods:
- Utilized *in vivo* studies in *Saccharomyces cerevisiae* to analyze the functional hierarchy of MLH complexes.
- Assessed the impact of mutations in different MLH complexes (Mlh1-Pms1, Mlh1-Mlh2, Mlh1-Mlh3) on MMR and CAG expansion rates.
- Investigated synergistic effects of mutations in *PMS1* and *MLH3*.
Main Results:
- Mlh1-Pms1 was identified as the primary MLH complex for Msh2-Msh3-mediated MMR.
- All three MLH complexes (Mlh1-Pms1, Mlh1-Mlh2, Mlh1-Mlh3) were essential for promoting CAG expansions.
- Loss of Mlh1-Pms1 or Mlh1-Mlh2 showed the most significant impact on CAG expansions; *PMS1* and *MLH3* mutations were synergistic.
Conclusions:
- Proposed a model where Mlh1-Pms1 handles standard Msh2-Msh3-mediated MMR, while a collaborative effort of all three MLH complexes promotes pathogenic CAG expansions.
- Highlighted the critical role of DNA structure-specific conformations in modulating MLH complex function during MMR and repeat expansion.
- This research provides insights into the distinct mechanisms governing genome stability versus disease-associated repeat instability.
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