Mild replication stress causes chromosome mis-segregation via premature centriole disengagement

Article Article scientifique Article Mild replication stress causes chromosome mis-segregation via premature centriole disengagement eng 2019 author Wilhelm Thérèse 835677 author Olziersky Anna-Maria 819839 author Harry Daniela 23513 author Fernandes De Sousa Filipe 917700 author Vassal Hélène 882234 author Eskat Anja 799851 author Meraldi Patrick 0000-0001-9742-8756 108140 3585 10.1038/s41467-019-11584-0 31395887 2041-1723 http://www.nature.com/articles/s41467-019-11584-0 Replication stress, a hallmark of cancerous and pre-cancerous lesions, is linked to structuralchromosomal aberrations. Recent studies demonstrated that it could also lead to numericalchromosomal instability (CIN). The mechanism, however, remains elusive. Here, we showthat inducing replication stress in non-cancerous cells stabilizes spindle microtubules andfavours premature centriole disengagement, causing transient multipolar spindles that lead tolagging chromosomes and micronuclei. Premature centriole disengagement depends on theG2 activity of the Cdk, Plk1 and ATR kinases, implying a DNA-damage induced deregulationof the centrosome cycle. Premature centriole disengagement also occurs spontaneously insome CIN+cancer cell lines and can be suppressed by attenuating replication stress. Finally,we show that replication stress potentiates the effect of the chemotherapeutic agent taxol, byincreasing the incidence of multipolar cell divisions. We postulate that replication stress incancer cells induces numerical CIN via transient multipolar spindles caused by prematurecentriole disengagement. Dewey 612 Swiss National Science Foundation Investigating the role of the centrosome in the mitotic spindle 179413 CH Project funding Swiss National Science Foundation Investigating the global regulation of the mitotic spindle 160006 CH Project funding 134 Département de physiologie cellulaire et métabolisme 21C false 579 Groupe Meraldi Patrick (physiologie cellulaire et métabolisme) 922 Nature Communications 10 1 fbc6008b-1a6a-4e0f-a47c-827447918d72 Article (Published version) Public s41467-019-11584-0.pdf 5117229 application/pdf CC BY openAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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Mild replication stress causes chromosome mis-segregation via premature centriole disengagement	Nature Communications			2019	485	385

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Wilhelm, Thérèse