Web of Science: 45 cites, Scopus: 51 cites, Google Scholar: cites
Progressive Telomere Dysfunction Causes Cytokinesis Failure and Leads to the Accumulation of Polyploid Cells
Pampalona Sala, Judit (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Frías García, Cristina (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Tusell Padrós, Laura (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)
Genescà, A. (Anna) (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)

Data: 2012
Resum: 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. Chromosome instability leads to the accumulation of chromosome number and structure aberrations that have been suggested as necessary for neoplastic transformation. Telomeres, specialized DNA–protein complexes localized at the physical ends of linear chromosomes, are crucial for maintaining chromosome stability. Massive chromosomal instability may occur when cells continuously proliferate in the absence of specific telomere elongation mechanisms. Besides telomere dysfunction, it has been suggested that a transient phase of tetraploidization has a causative role in cancer. This study provides a link between dysfunctional telomeres and the generation of tetraploids. Using a human mammary epithelial cell model, we show that diploid cells exhibiting progressive telomere dysfunction, in a p53 proficient background, engender tetraploid cells through cytokinesis failure. Our studies give new insights into the mechanisms that may facilitate the evolution of malignant phenotypes: telomere-dependent chromosome instability would engender tetraploid intermediates that, on division, would promote further cellular genome remodelling, which is needed at the early stages of tumour development in order for cells to become neoplasic.
Nota: Número d'acord de subvenció ISCIII/RD06/0020/1020
Nota: Número d'acord de subvenció AGAUR/2009/SGR-282
Nota: Número d'acord de subvenció AGAUR/2008/FIC-00051
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès.
Document: article ; recerca ; publishedVersion
Publicat a: PLoS Genetics, Vol. 8, Issue 4 (April 2012) , ISSN 1553-7404

PMID: 22570622
DOI: 10.1371/journal.pgen.1002679


11 p, 1.2 MB

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