Annuaire
Aurèle PIAZZA
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Le 06/01/2023, de 11:00 à 12:00 |
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| S'adresser à | Equipe Piazza - Salle des Thèses |
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Punctuated bursts of structural genomic variations (SVs) has been described in various organisms, but their etiology remains incompletely understood. Homologous recombination (HR) operates the template-guided repair of DNA double-strand breaks and stalled or collapsed replication forks. We recently identified multi-invasion-induced rearrangement (MIR), a DNA break amplification and genome rearrangement mechanism originating from the endonucleolytic processing of a DNA joint molecule byproduct of homology search during HR. Using genome-wide approaches, we confirmed the propensity of MIR to initiate a cascade of repeat-mediated SVs and aneuploidies. Molecular and genetic analysis delineated two MIR sub-pathways. MIR1 is a universal pathway occurring in any sequence context, which generates secondary breaks and frequently leads to additional SVs. MIR2 occurs only if recombining donors exhibit substantial homology, and results in sequence insertion without additional break and SV. Kinetics analysis of DNA joint molecules and MIR product formation with highly sensitive proximity ligation-based molecular assays revealed that MIR1 occurs late on a subset of persisting DNA joint molecules. While initiation of recombinational DNA synthesis depends on PCNA-Pold, MIR1 does not. This work yields a refined mechanistic understanding of these HR-based SV formation pathways, and shows that tripartite repeat-mediated SVs can occur without displacement DNA synthesis.