TY - JOUR T1 - Cytological and genetic consequences for the progeny of a mitotic catastrophe provoked by Topoisomerase II deficiency JF - bioRxiv DO - 10.1101/668954 SP - 668954 AU - Cristina Ramos-Pérez AU - Margaret Dominska AU - Laura Anaissi-Afonso AU - Sara Cazorla-Rivero AU - Oliver Quevedo AU - Isabel Lorenzo-Castrillejo AU - Thomas D Petes AU - Félix Machín Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/06/13/668954.abstract N2 - The interplay between regulated cell death (RCD) and mitotic catastrophe (MC) determines much of the success of many anticancer treatments. Down-regulation of Topoisomerase II (Top2) is the more direct and devastating form of MC since it happens concomitantly with the formation of anaphase bridges in cells proficient for G2/M checkpoints. Herein, we have characterized in budding yeast the consequences for the cell progeny of a top2 MC. Clonogenic and microcolony experiments, in combination with vital stains, showed that 75% of daughter cells become senescent immediately after the top2 MC; they are unable to divide but remain alive. Decline in cell vitality occurred slowly, not even reaching 50% of cells 24 h after the MC, and uncoordinatedly when comparing pairs of daughters. Genetic experiments showed that the RCD mediator Mca1/Yca1 does not modify the senescence/death outcome. We thus conclude that MC mediated by Top2 deficiency leads to short-term senescence that eventually ends up in non-regulated cell death. Furthermore, we showed that the ability to divide in the short term can be modulated by the chromosome ploidy, suggesting that gross chromosome imbalances during segregation may account for senescence in the top2 progeny. Indeed, we found that diploid long-term survivors of the top2 MC are prone to genomic imbalances such as trisomies, uniparental disomies and terminal loss of heterozygosity (LOH), the latter affecting the longest chromosome arms. ER -