Telomere-Driven Tetraploidization Occurs in Human Cells Undergoing Crisis and Promotes Transformation of Mouse Cells
Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel un dysfonctionnement des télomères, en induisant la formation de cellules tétraploïdes, favorise la tumorigenèse
Human cancers with a subtetraploid karyotype are thought to originate from tetraploid precursors, but the cause of tetraploidization is unknown. We previously documented endoreduplication in mouse cells with persistent telomere dysfunction or genome-wide DNA damage. We now report that endoreduplication and mitotic failure occur during telomere crisis in human fibroblasts and mammary epithelial cells and document the role of p53 and Rb in repressing tetraploidization. Using an inducible system to generate transient telomere damage, we show that telomere-driven tetraploidization enhances the tumorigenic transformation of mouse cells. Similar to human solid cancers, the resulting tumors evolved subtetraploid karyotypes. These data establish that telomere-driven tetraploidization is induced by critically short telomeres and has the potential to promote tumorigenesis in early cancerous lesions. º Human fibroblasts and mammary epithelial cells can become tetraploid in telomere crisis º Tetraploidization in telomere crisis is due to endoreduplication and mitotic failure º The Rb pathway contributes to repression of telomere-driven tetraploidization º Telomere-driven tetraploidization promotes tumorigenic transformation of mouse cells
Cancer cell , résumé, 2011