Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation - I2BC Accéder directement au contenu
Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2021

Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation

Jingqi Dai
Aurore Sanchez
  • Fonction : Auteur
Céline Adam
  • Fonction : Auteur
Lepakshi Ranjha
  • Fonction : Auteur
Giordano Reginato
  • Fonction : Auteur
Pierre Chervy
Carine Tellier-Lebegue
  • Fonction : Auteur
Jessica Andreani
Raphaël Guérois
Virginie Ropars
Marie-Hélène Le Du
  • Fonction : Auteur
Laurent Maloisel
  • Fonction : Auteur
Emmanuelle Martini
Pierre Legrand
Aurélien Thureau
Petr Cejka
  • Fonction : Auteur
Valérie Borde

Résumé

In budding yeast, the MutL homolog heterodimer Mlh1-Mlh3 (MutLγ) 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 (MutLα). The heterodimer interface and endonuclease sites of MutLγ and MutLα are located in their C-terminal domain (CTD). The molecular basis of MutLγ’s dual roles in MMR and meiosis is not known. To better understand the specificity of MutLγ, we characterized the crystal structure of Saccharomyces cerevisiae MutLγ(CTD). Although MutLγ(CTD) presents overall similarities with MutLα(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 MutLγ(CTD) preferentially binds Holliday junctions, contrary to MutLα(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 MutLγ. Finally, crystal packing revealed an assembly of MutLγ(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 MutLγ. This study defines clear divergent features between the MutL homologs and identifies, at the molecular level, their specialization toward MMR or meiotic recombination functions.

Dates et versions

hal-03454666 , version 1 (29-11-2021)

Identifiants

Citer

Jingqi Dai, Aurore Sanchez, Céline Adam, Lepakshi Ranjha, Giordano Reginato, et al.. Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation. Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (23), pp.e2022704118. ⟨10.1073/pnas.2022704118⟩. ⟨hal-03454666⟩
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