Regulation of the MLH1-MLH3 endonuclease in meiosis. - Institut Curie Accéder directement au contenu
Article Dans Une Revue Nature Année : 1970

Regulation of the MLH1-MLH3 endonuclease in meiosis.

Elda Cannavo
  • Fonction : Auteur
Aurore Sanchez
  • Fonction : Auteur
Roopesh Anand
  • Fonction : Auteur
Lepakshi Ranjha
  • Fonction : Auteur
Jannik Hugener
  • Fonction : Auteur
Céline Adam
  • Fonction : Auteur
Ananya Acharya
  • Fonction : Auteur
Nicolas Weyland
  • Fonction : Auteur
Xavier Aran-Guiu
  • Fonction : Auteur
Jean-Baptiste Charbonnier
Eva Hoffmann
  • Fonction : Auteur
Valérie Borde
Joao Matos
  • Fonction : Auteur
Petr Cejka
  • Fonction : Auteur

Résumé

During prophase of the first meiotic division, cells deliberately break their DNA1. These DNA breaks are repaired by homologous recombination, which facilitates proper chromosome segregation and enables the reciprocal exchange of DNA segments between homologous chromosomes2. A pathway that depends on the MLH1-MLH3 (MutLγ) nuclease has been implicated in the biased processing of meiotic recombination intermediates into crossovers by an unknown mechanism3-7. Here we have biochemically reconstituted key elements of this pro-crossover pathway. We show that human MSH4-MSH5 (MutSγ), which supports crossing over8, binds branched recombination intermediates and associates with MutLγ, stabilizing the ensemble at joint molecule structures and adjacent double-stranded DNA. MutSγ directly stimulates DNA cleavage by the MutLγ endonuclease. MutLγ activity is further stimulated by EXO1, but only when MutSγ is present. Replication factor C (RFC) and the proliferating cell nuclear antigen (PCNA) are additional components of the nuclease ensemble, thereby triggering crossing-over. Saccharomyces cerevisiae strains in which MutLγ cannot interact with PCNA present defects in forming crossovers. Finally, the MutLγ-MutSγ-EXO1-RFC-PCNA nuclease ensemble preferentially cleaves DNA with Holliday junctions, but shows no canonical resolvase activity. Instead, it probably processes meiotic recombination intermediates by nicking double-stranded DNA adjacent to the junction points9. As DNA nicking by MutLγ depends on its co-factors, the asymmetric distribution of MutSγ and RFC-PCNA on meiotic recombination intermediates may drive biased DNA cleavage. This mode of MutLγ nuclease activation might explain crossover-specific processing of Holliday junctions or their precursors in meiotic chromosomes4.

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Elda Cannavo, Aurore Sanchez, Roopesh Anand, Lepakshi Ranjha, Jannik Hugener, et al.. Regulation of the MLH1-MLH3 endonuclease in meiosis.. Nature, 1970, 586 (7830), pp.618-622. ⟨10.1038/s41586-020-2592-2⟩. ⟨hal-03020381⟩

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