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Article | Scientific result | Simulation ＆ modelling | Structural biology | Molecular mechanisms
In a study conducted by a team from the Institut Curie, researchers from the CEA-Joliot (B3S/I2BC department) have modeled in silico protein-protein interactions and thus contributed to establish at the molecular level the mechanisms that coordinate the pairing and recombination of homologous chromosomes during meiosis.
Meiosis leads to the separation of homologous chromosomes in germline cells, so that each gamete inherits only one copy (maternal or paternal) of each chromosome. One of the steps in this segregation involves simultaneously pairing the homologous chromosomes along their entire length (like a zipper), thanks to the synaptonemal complex, and establishing "contact points" between them to make them crossover and recombine. Researchers from the Institut Curie (V. Borde's team) and the "Molecular Assemblies and Genome Integrity" team (AMIG, I2BC department) have identified the molecular basis of the mechanisms linking pairing and homologous recombination in Saccharomyces cerevisiae, which are highly conserved from yeast to humans.
They showed that the Ecm11 protein of the synaptonemal complex interacts with Zip4, one of the proteins required for homologous chromosome spacing. In vivo, Ecm11 would be localized at recombination sites and along the chromosome axis only in the presence of Zip4. Thanks to advanced sequence analysis and structure prediction methods using artificial intelligence, researchers from the CEA's AMIG team have generated structural models of Zip4 and Ecm11 and proposed point mutations of the two proteins that destabilize their interaction. In addition to abolishing the Zip4-Ecm11 interaction, the mutants expressed in vivo prevent the binding of Ecm11 to chromosomes and render the assembly of the synaptonemal complex and chromosome pairing defective. In patients with azoospermia, it was recently discovered that the Zip4 protein was mutated at a particular position. This position is precisely at the Ecm11 binding site, suggesting that problems in the assembly of the synaptonemal complex may be at the origin of this pathology.
This study suggests that the fine control of recombination frequency and crossover distribution by the synaptonemal complex is initiated by the direct interaction between Zip4 and Ecm11.
Alexandra Pyatnitskaya, Jessica Andreani, Raphaël Guérois, Arnaud De Muyt and Valérie Borde. The Zip4 protein directly couples meiotic crossover formation to
synaptonemal complex assembly. | Genes & Dev, 2021
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.