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Mol Biol Cell. 2014 Oct 15;25(20):3105-18. doi: 10.1091/mbc.E14-03-0844. Epub 2014 Aug 20.

Failure of cell cleavage induces senescence in tetraploid primary cells.

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Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037.
Department of Immunology and Oncology, Centro Nacional de Biotecnologia, Consejo Superior de Investigaciones Científicas, E-28049 Madrid, Spain.
San Diego Heart Research Institute and Department of Biology; San Diego State University, San Diego, CA 92182.
Tumor Initiation and Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037


Tetraploidy can arise from various mitotic or cleavage defects in mammalian cells, and inheritance of multiple centrosomes induces aneuploidy when tetraploid cells continue to cycle. Arrest of the tetraploid cell cycle is therefore potentially a critical cellular control. We report here that primary rat embryo fibroblasts (REF52) and human foreskin fibroblasts become senescent in tetraploid G1 after drug- or small interfering RNA (siRNA)-induced failure of cell cleavage. In contrast, T-antigen-transformed REF52 and p53+/+ HCT116 tumor cells rapidly become aneuploid by continuing to cycle after cleavage failure. Tetraploid primary cells quickly become quiescent, as determined by loss of the Ki-67 proliferation marker and of the fluorescent ubiquitination-based cell cycle indicator/late cell cycle marker geminin. Arrest is not due to DNA damage, as the γ-H2AX DNA damage marker remains at control levels after tetraploidy induction. Arrested tetraploid cells finally become senescent, as determined by SA-β-galactosidase activity. Tetraploid arrest is dependent on p16INK4a expression, as siRNA suppression of p16INK4a bypasses tetraploid arrest, permitting primary cells to become aneuploid. We conclude that tetraploid primary cells can become senescent without DNA damage and that induction of senescence is critical to tetraploidy arrest.

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