Progressive Telomere Dysfunction Causes Cytokinesis Failure and Leads to the Accumulation of Polyploid Cells

Most cancer cells accumulate genomic abnormalities at a remarkably rapid rate, as they are unable to maintain their chromosome structure and number. Excessively short telomeres, a known source of chromosome instability, are observed in early human-cancer lesions. Besides telomere dysfunction, it has been suggested that a transient phase of polyploidization, in most cases tetraploidization, has a causative role in cancer. Proliferation of tetraploids can gradually generate subtetraploid lineages of unstable cells that might fire the carcinogenic process by promoting further aneuploidy and genomic instability. Given the significance of telomere dysfunction and tetraploidy in the early stages of carcinogenesis, we investigated whether there is a connection between these two important promoters of chromosomal instability. We report that human mammary epithelial cells exhibiting progressive telomere dysfunction, in a pRb deficient and wild-type p53 background, fail to complete the cytoplasmatic cell division due to the persistence of chromatin bridges in the midzone. Flow cytometry together with fluorescence in situ hybridization demonstrated an accumulation of binucleated polyploid cells upon serial passaging cells. Restoration of telomere function through hTERT transduction, which lessens the formation of anaphase bridges by recapping the chromosome ends, rescued the polyploid phenotype. Live-cell imaging revealed that these polyploid cells emerged after abortive cytokinesis due to the persistence of anaphase bridges with large intervening chromatin in the cleavage plane. In agreement with a primary role of anaphase bridge intermediates in the polyploidization process, treatment of HMEC-hTERT cells with bleomycin, which produces chromatin bridges through illegimitate repair, resulted in tetraploid binucleated cells. Taken together, we demonstrate that human epithelial cells exhibiting physiological telomere dysfunction engender tetraploid cells through interference of anaphase bridges with the completion of cytokinesis. These observations shed light on the mechanisms operating during the initial stages of human carcinogenesis, as they provide a link between progressive telomere dysfunction and tetraploidy

Dispositif d'étude des décharges couronnes dans les gaz à pression élevée ou liquéfiés

An electronic device for the study of the pulse regime in liquified gases (argon, krypton, nitrogen) is described. The charge per pulse (duration up to 30 $\mu$s) and the elapsed time between two successive pulses can be measured. These measured values (up to 60 series of 1 000 values each) are transfered to and processed on a microcomputer. Moreover, the simultaneous measurement of these charges and elapsed times makes it possible to check for correlations between these quantities. By using this device for the study of liquified and compressed gases we demonstrate that a self-sustaining and self-stabilizing discharge occurs both in high pressure gas and liquid phases.Nous présentons un dispositif électronique pour l'étude des régimes d'impulsions de courant dans les gaz liquéfiés (argon, krypton, azote). Il permet la mesure de la charge des impulsions de courant, d'une durée pouvant atteindre 30 $\mu$s, et des temps séparant deux impulsions successives. Les valeurs mesurées (jusqu'à 60 séries de 1 000 valeurs chacune) sont transférées et traitées dans un micro-ordinateur. D'autre part la saisie simultanée des charges et des intervalles de temps permet une analyse des corrélations éventuelles entre ces grandeurs. L'utilisation de ce dispositif pour l'étude des composés liquides et gazeux nous a permis de montrer qu'un régime de décharges auto-entretenues et auto-stabilisées par la charge d'espace se produit aussi bien dans le gaz sous pression que dans la phase liquide

Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes

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