Exo1 recruits Cdc5 polo kinase to MutLγ to ensure efficient meiotic crossover formation.

Aurore Sanchez , Céline Adam , Felix Rauh , Yann Duroc , Lepakshi Ranjha , Bérangère Lombard , Xiaojing Mu , Mélody Wintrebert , Damarys Loew , Alba Guarné , Stefano Gnan , Chun-Long Chen , Scott Keeney , Petr Cejka , Raphaël Guérois , Franz Klein , Jean-Baptiste Charbonnier , Valérie Borde (1)

1 Institut Curie [Paris]

Crossovers generated during the repair of programmed meiotic double-strand breaks must be tightly regulated to promote accurate homolog segregation without deleterious outcomes, such as aneuploidy. The Mlh1-Mlh3 (MutLγ) endonuclease complex is critical for crossover resolution, which involves mechanistically unclear interplay between MutLγ and Exo1 and polo kinase Cdc5. Using budding yeast to gain temporal and genetic traction on crossover regulation, we find that MutLγ constitutively interacts with Exo1. Upon commitment to crossover repair, MutLγ-Exo1 associate with recombination intermediates, followed by direct Cdc5 recruitment that triggers MutLγ crossover activity. We propose that Exo1 serves as a central coordinator in this molecular interplay, providing a defined order of interaction that prevents deleterious, premature activation of crossovers. MutLγ associates at a lower frequency near centromeres, indicating that spatial regulation across chromosomal regions reduces risky crossover events. Our data elucidate the temporal and spatial control surrounding a constitutive, potentially harmful, nuclease. We also reveal a critical, noncatalytic role for Exo1, through noncanonical interaction with polo kinase. These mechanisms regulating meiotic crossovers may be conserved across species.

Mots clés: MutL; crossovers; meiosis; polo kinase; recombination

Domaines: Sciences du Vivant [q-bio]

Aurore Sanchez, Céline Adam, Felix Rauh, Yann Duroc, Lepakshi Ranjha, et al.. Exo1 recruits Cdc5 polo kinase to MutLγ to ensure efficient meiotic crossover formation.. Proceedings of the National Academy of Sciences of the United States of America, 2020, ⟨10.1073/pnas.2013012117⟩. ⟨hal-03020386⟩