The unstructured linker of Mlh1 contains a motif required for endonuclease function which is mutated in cancers.

Eukaryotic DNA mismatch repair (MMR) depends on recruitment of the Mlh1-Pms1 endonuclease (human MLH1-PMS2) to mispaired DNA. Both Mlh1 and Pms1 contain a long unstructured linker that connects the N- and carboxyl-terminal domains. Here, we demonstrated the Mlh1 linker contains a conserved motif (Saccharomyces cerevisiae residues 391-415) required for MMR. ...
The Mlh1-R401A,D403A-Pms1 linker motif mutant protein was defective for MMR and endonuclease activity in vitro, even though the conserved motif could be >750 A from the carboxyl-terminal endonuclease active site or the N-terminal adenosine triphosphate (ATP)-binding site. Peptides encoding this motif inhibited wild-type Mlh1-Pms1 endonuclease activity. The motif functioned in vivo at different sites within the Mlh1 linker and within the Pms1 linker. Motif mutations in human cancers caused a loss-of-function phenotype when modeled in S. cerevisiae. These results suggest that the Mlh1 motif promotes the PCNA-activated endonuclease activity of Mlh1-Pms1 via interactions with DNA, PCNA, RFC, or other domains of the Mlh1-Pms1 complex.
Mesh Terms:
Adenosine Triphosphate, DNA, DNA Mismatch Repair, DNA-Binding Proteins, Endonucleases, Humans, Mismatch Repair Endonuclease PMS2, MutL Protein Homolog 1, MutL Proteins, MutS Homolog 2 Protein, Mutant Proteins, Neoplasms, Proliferating Cell Nuclear Antigen, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins
Proc Natl Acad Sci U S A
Date: Oct. 18, 2022
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