6shx
DNA mismatch repair proteins MLH1 and MLH3
Structural highlights
FunctionMLH1_YEAST Required for DNA mismatch repair (MMR), correcting base-base mismatches and insertion-deletion loops (IDLs) resulting from DNA replication, DNA damage or from recombination events between non-identical sequences during meiosis. Component of different MutL heterodimers that form a ternary complex with the MutS heterodimers, which initially recognize the DNA mismatches. This complex is thought to be responsible for directing the downsteam MMR events, including strand discrimination, excision, and resynthesis. Plays a major role in maintaining the genetic stability of simple sequence repeats, the repair of heteroduplex sites present in meiotic recombination intermediates, and the promotion of meiotic crossing-over.[1] [2] [3] Publication Abstract from PubMedIn budding yeast, the MutL homolog heterodimer Mlh1-Mlh3 (MutLgamma) plays a central role in the formation of meiotic crossovers. It is also involved in the repair of a subset of mismatches besides the main mismatch repair (MMR) endonuclease Mlh1-Pms1 (MutLalpha). The heterodimer interface and endonuclease sites of MutLgamma and MutLalpha are located in their C-terminal domain (CTD). The molecular basis of MutLgamma's dual roles in MMR and meiosis is not known. To better understand the specificity of MutLgamma, we characterized the crystal structure of Saccharomyces cerevisiae MutLgamma(CTD). Although MutLgamma(CTD) presents overall similarities with MutLalpha(CTD), it harbors some rearrangement of the surface surrounding the active site, which indicates altered substrate preference. The last amino acids of Mlh1 participate in the Mlh3 endonuclease site as previously reported for Pms1. We characterized mlh1 alleles and showed a critical role of this Mlh1 extreme C terminus both in MMR and in meiotic recombination. We showed that the MutLgamma(CTD) preferentially binds Holliday junctions, contrary to MutLalpha(CTD). We characterized Mlh3 positions on the N-terminal domain (NTD) and CTD that could contribute to the positioning of the NTD close to the CTD in the context of the full-length MutLgamma. Finally, crystal packing revealed an assembly of MutLgamma(CTD) molecules in filament structures. Mutation at the corresponding interfaces reduced crossover formation, suggesting that these superstructures may contribute to the oligomer formation proposed for MutLgamma. This study defines clear divergent features between the MutL homologs and identifies, at the molecular level, their specialization toward MMR or meiotic recombination functions. Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation.,Dai J, Sanchez A, Adam C, Ranjha L, Reginato G, Chervy P, Tellier-Lebegue C, Andreani J, Guerois R, Ropars V, Le Du MH, Maloisel L, Martini E, Legrand P, Thureau A, Cejka P, Borde V, Charbonnier JB Proc Natl Acad Sci U S A. 2021 Jun 8;118(23):e2022704118. doi: , 10.1073/pnas.2022704118. PMID:34088835[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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