RAD51 and its partners in Meiosis-specific mechanisms of Homologous Recombination

• Auteur / Autrice : Léa Guiraud
• Direction : Pauline Dupaigne
• Type : Projet de thèse
• Discipline(s) : Sciences du Cancer
• Date : Inscription en doctorat le 01/10/2024
• Etablissement(s) : université Paris-Saclay
• Ecole(s) doctorale(s) : École doctorale Cancérologie, Biologie, Médecine, Santé
• Partenaire(s) de recherche : Laboratoire : Intégrité du Génome et Cancers
• Partenaire(s) de recherche : Référent : Faculté de médecine

Mots clés

Mots clés libres

Réparation de l'ADN

Brca2

Méiose

Recombinaison homologue

Brca2

Meiosis

Homologous recombination

DNA Repair

Résumé

Homologous recombination (HR) is a widely conserved mechanism essential for genome integrity. In somatic cells, HR is a key player to release replication stresses. In germ cells, HR is essential to produce viable gametes and create genetic diversity in progenies. Consequently, defective HR induces genome instability in somatic and germinal cells. Mutation and deregulated expression of HR genes are associated with tumorigenesis and infertility. Recombination is based on a genetic exchange mechanism at the heart of which are the RAD51 and DMC1 recombinases and their partner proteins, including the BRCA2 mediator protein. Their assembly on the DNA to form the presynaptic filament is responsible for homology search and homologous pairing to ensure genetic exchange, a finely regulated step. In mitotic cells, DNA repair by HR occurs between sister chromatids to minimize genomic rearrangements, whereas in meiotic prophase I, HR occurs between homologous chromosomes to form a physical connection between them, ensure proper chromosome segregation and eventually lead to genetic exchange (aka crossover, CO). Despite these differences, meiotic HR can be defined as a “specialization” of HR, as their main steps are similar, but meiotic HR uses a combination of HR and meiosis-specific factors to ensure its specific outcomes. In order to establish meiosis-specific mechanisms, a set of proteins is specifically expressed in germ cells during prophase I of meiosis. In the first steps of HR, SPATA22, MEIOB, HSF2BPMEILB2 and BRME1 influence recombinases recruitment and dynamics. A defect in one of these meiotic proteins can significantly decrease the production of gametes and reduce fertility. Also, these proteins are identified as Cancer Testis Antigens: they can be mis-expressed in cancer cells, interfere with somatic HR and contribute to genome instability. However, the functions of these proteins are poorly described. This thesis project is part of a well-funded collaborative program with the aim of combining in vivo, biochemical, and structural methods, to understand how meiosis specific proteins, recently identified, control the formation and the activity of the central player of HR, the synaptic filament, during meiotic HR. This axis will use biochemical, transmission electron microscopy and cryomicroscopy approaches to better understand how these proteins act on DNA.