Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells.
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.
Laboratory for Genetics and Cell Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Teresa
T
Davoli
Titia
T
de Lange
D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D059785:Karyotype; D042361:Mammary Glands, Human / Q000166:cytology; D051379:Mice; D008938:Mitosis / Q000235:genetics; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D057891:Tetraploidy; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53