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Mlh1-Pms1 couples ATP-driven DNA compaction with nick-dependent endonuclease activation
Bryce W Collingwood1, Amruta N Bhalkar1, Carol M Manhart1
1Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
Nucleic Acids Research
|December 3, 2025
Summary
DNA mismatch repair uses ATP to compact DNA, aiding mismatch detection. This process shifts to a repair mode when encountering nicks, stabilizing the site for efficient DNA repair.
Area of Science:
- Molecular Biology
- DNA Repair Mechanisms
- Biochemistry
Background:
- Eukaryotic DNA mismatch repair (MMR) involves MutS homolog (MSH) and Mlh1-Pms1/PMS2 complexes.
- Mlh1-Pms1/PMS2 nicks DNA to facilitate mismatch removal by downstream proteins.
- The ATPase activity of Mlh1-Pms1 is essential in vivo but not for in vitro nicking, leaving its function unclear.
Purpose of the Study:
- To elucidate the unresolved function of Mlh1-Pms1's ATPase activity in DNA mismatch repair.
- To investigate the mechanism by which Mlh1-Pms1 interacts with DNA and other repair factors.
Main Methods:
- Utilized yeast proteins to study Mlh1-Pms1 function in vitro.
- Employed DNA compaction assays to observe Mlh1-Pms1 behavior on continuous DNA.
- Conducted phased nicking assays to analyze Mlh1-Pms1 activation dynamics with replication factor C (RFC)/PCNA.
Main Results:
- Mlh1-Pms1 uses ATP to compact continuous DNA, potentially serving as a search mechanism.
- DNA nicking suppresses Mlh1-Pms1 compaction, leading to site stabilization.
- The timing of Mlh1-Pms1 encountering a nick relative to RFC/PCNA dictates its activation state.
Conclusions:
- Mlh1-Pms1 utilizes ATP-driven DNA compaction to switch between a DNA search mode and a PCNA-licensed repair mode.
- This dynamic switching mechanism is crucial for efficient and accurate DNA mismatch repair.
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