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Mlh1-Pms1 ATPase activity is regulated distinctly by self-generated nicks and strand discrimination signals in mismatch repair
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2024-12-20 , DOI: 10.1093/nar/gkae1253 Jonathan M Piscitelli, Scott J Witte, Yasmine S Sakinejad, Carol M Manhart
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2024-12-20 , DOI: 10.1093/nar/gkae1253 Jonathan M Piscitelli, Scott J Witte, Yasmine S Sakinejad, Carol M Manhart
In eukaryotic post-replicative mismatch repair, MutS homolog complexes detect mismatches and in the major eukaryotic pathway, recruit Mlh1-Pms1/MLH1-PMS2 (yeast/human) complexes, which nick the newly replicated DNA strand upon activation by the replication processivity clamp, PCNA. This incision enables mismatch removal and DNA repair. Beyond its endonuclease role, Mlh1-Pms1/MLH1-PMS2 also has ATPase activity, which genetic studies suggest is essential for mismatch repair, although its precise regulatory role on DNA remains unclear. Here, we use an ATP-binding and hydrolysis-deficient yeast Mlh1-Pms1 variant to show that ATP hydrolysis promotes disengagement from Mlh1-Pms1-generated nicks, with hydrolysis in the Mlh1 subunit driving this activity. Our data suggest that the ATPase-deficient variant becomes trapped on its own endonuclease product, suggesting a mechanistic explanation for observations in genetic experiments. Additionally, we observed that Mlh1-Pms1 selectively protects DNA from exonuclease degradation at pre-existing nicks, which may act as strand discrimination signals in mismatch repair. Together, our findings suggest that Mlh1-Pms1 exhibits distinct behaviors on its own endonuclease products versus substrates with pre-existing nicks, supporting two distinct modes of action during DNA mismatch repair.
更新日期：2024-12-20
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