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Rôles des télomères internes et des condensines dans la cassure des chromosomes dicentriques par la cytodiérèse chez Saccharomyces cerevisiae

Abstract : Telomeres ensure chromosome end stability. Failure to do so would lead to chromosome end fusions and the formation dicentric chromosomes (i.e. chromosomes with two centromeres) that are unstable in mitosis. Dicentrics are a threat to cell viability and a source of extensive mutagenesis. In Saccharomyces cerevisiae, dicentrics formed by telomere fusion preferentially break at the fusion. This unexplained process allows the recovery of a normal karyotype and protects the genome from the detrimental consequences of accidental telomere fusions. Here, I address the molecular basis of this rescue pathway. Simple tandem arrays tightly bound by the telomere factor Rap1 or a heterologous high-affinity DNA binding factor are sufficient to establish breakage hotspots, mimicking telomere fusions within dicentrics. I also adress the mechanism allowing breakage at pericentromeric regions when dicentric do not bear telomeric sequences. During anaphase, Condensins generate forces sufficient to rapidly relocalize the centromeres to the bud neck and refold dicentrics prior their breakage by cytokinesis. This relocalisation is essential for breakage at pericentromeres. Moreover Condensin-dependent refolding is essential to the preferential breakage at telomere fusions, more generally at Rap1-bound arrays and which delimit insulated chromosomal domains. Thus, the rescue of fused telomeres results from a Condensin- and Rap1-driven chromosome conformation that favours fusion entrapment where the septum closes. These results suggest that Rap1-bound telomere sequences stall loop-extrusion by Condensins. In addition, this work provides a new and direct way to monitor Condensin activity on chromatin in live cells. It also shows that dicentric chromosomes are broken during septation and that cytokinesis is not delayed by chromatin bridges.
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Thomas Guérin. Rôles des télomères internes et des condensines dans la cassure des chromosomes dicentriques par la cytodiérèse chez Saccharomyces cerevisiae. Biologie moléculaire. Université Paris Saclay (COmUE), 2018. Français. ⟨NNT : 2018SACLS581⟩. ⟨tel-02426254⟩

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