Public Thesis Defense - LIBST

The biomolecular interactions of Rec114-Mei4 and Mer2 in the assembly of the meiotic DNA double-strand break machinery by Dima Aldaccache

Pour l’obtention du grade académique de Doctorat en Sciences

Meiosis is a special type of cell division that occurs in all eukaryotes with sexual reproduction and generates haploid gametes from diploid germ cells. During meiosis, the formation of DNA double strand breaks (DSBs) by Spo11 triggers a mechanism of DNA recombination that is essential for the accurate pairing and segregation of homologous chromosomes.

S. cerevisiae Rec114-Mei4 and Mer2 (RMM) are essential partners of Spo11 that ensure its recruitment to meiotic chromosomes, a role that is conserved in higher eukaryotes. A previous biochemical characterization of RMM proteins showed that they form two sub-complexes that bind DNA with remarkable cooperativity to assemble macromolecular structures that contains hundreds or thousands of proteins, which we refer to as condensates.

Our hypothesis is that the RMM proteins assemble large nucleoprotein clusters along the chromosomes, and that these macromolecular structures create an assembly platform that recruits Spo11 and other partners prior to DSB formation.

During my thesis, I aimed to shed light onto the mechanism of RMM proteins, using biochemistry, biophysics, structural biology and molecular genetics approaches in yeast. I studied the structure of RMM proteins which helped me establish the protein-protein and protein-DNA interactions involved in the assembly of RMM condensates. This revealed that RMM proteins undergo multivalent interactions with DNA which is an essential driver of condensation. The Rec114-Mei4 and Mer2 structures are evolutionarily conserved across eukaryotes, though their DNA-binding properties exhibit substantial variation. In addition, I investigated the control of the formation and dissociation of condensates by RMM phosphorylation. The phosphorylation of Mer2 enhances its inter-tetrameric protein-protein interaction while the phosphorylation of Rec114 seems to decrease its condensation activity. In addition, I established that Rec114 and Mer2 interact through their PH domain and conserved SSM1 motifs, respectively. These findings provide novel insights into the assembly and regulation of the DSB machinery, which is fundamental to the correct execution of meiosis.

Jury members :

• Prof. Corentin Claeys Bouuaert (UCLouvain), Supervisor
• Prof. Bernard Hallet (UCLouvain), Chairperson
• Prof. Pierre Morsomme (UCLouvain), Secretary
• Prof. Patrice Soumillion (UCLouvain)
• Prof. Petr Cejka (IRB, Bellinzona)
• Prof. Matt Neale (University of Sussex)

Pay attention : the public defense of Dima Aldaccache will also take place in the form of a videoconference

Télécharger l'annonce