Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation
| Autor: | Lepakshi Ranjha, Pierre Chervy, Valérie Borde, Marie-Hélène Le Du, Laurent Maloisel, Jean-Baptiste Charbonnier, Giordano Reginato, Aurélien Thureau, Virginie Ropars, Emmanuelle Martini, Pierre Legrand, Jessica Andreani, Aurore Sanchez, Céline Adam, Petr Cejka, Jingqi Dai, Raphael Guerois, Carine Tellier-Lebegue |
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| Přispěvatelé: | Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular congenital hereditary and neonatal diseases and abnormalities Saccharomyces cerevisiae Proteins DNA Repair [SDV]Life Sciences [q-bio] Saccharomyces cerevisiae Context (language use) MLH3 MLH1 environment and public health DNA Mismatch Repair 03 medical and health sciences Holliday junction 030304 developmental biology 0303 health sciences Multidisciplinary Binding Sites biology Chemistry 030302 biochemistry & molecular biology fungi Recombinational DNA Repair Biological Sciences biology.organism_classification Endonucleases Cell biology DNA-Binding Proteins enzymes and coenzymes (carbohydrates) Meiosis MutL Proteins DNA mismatch repair CTD Homologous recombination MutL Protein Homolog 1 |
| Zdroj: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2021, 118 (23), pp.e2022704118. ⟨10.1073/pnas.2022704118⟩ Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (23), pp.e2022704118. ⟨10.1073/pnas.2022704118⟩ |
| ISSN: | 0027-8424 1091-6490 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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