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  Abnormal mitosis triggers p53-dependent cell cycle arrest in human tetraploid cells

Kuffer, C., Kuznetsova, A. Y., & Storchova, Z. (2013). Abnormal mitosis triggers p53-dependent cell cycle arrest in human tetraploid cells. CHROMOSOMA, 122(4), 305-318. doi:10.1007/s00412-013-0414-0.

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 Creators:
Kuffer, Christian1, Author           
Kuznetsova, Anastasia Yurievna1, Author           
Storchova, Zuzana1, Author           
Affiliations:
1Storchova, Zuzana / Maintenance of Genome Stability, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565171              

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Free keywords: EXTRA CENTROSOMES; MAMMALIAN-CELLS; CHROMOSOMAL INSTABILITY; CYTOKINESIS FAILURE; OXIDATIVE STRESS; CLEAVAGE FAILURE; SOMATIC-CELLS; DNA-DAMAGE; CHECKPOINT; ANEUPLOIDY
 Abstract: Erroneously arising tetraploid mammalian cells are chromosomally instable and may facilitate cell transformation. An increasing body of evidence shows that the propagation of mammalian tetraploid cells is limited by a p53-dependent arrest. The trigger of this arrest has not been identified so far. Here we show by live cell imaging of tetraploid cells generated by an induced cytokinesis failure that most tetraploids arrest and die in a p53-dependent manner after the first tetraploid mitosis. Furthermore, we found that the main trigger is a mitotic defect, in particular, chromosome missegregation during bipolar mitosis or spindle multipolarity. Both a transient multipolar spindle followed by efficient clustering in anaphase as well as a multipolar spindle followed by multipolar mitosis inhibited subsequent proliferation to a similar degree. We found that the tetraploid cells did not accumulate double-strand breaks that could cause the cell cycle arrest after tetraploid mitosis. In contrast, tetraploid cells showed increased levels of oxidative DNA damage coinciding with the p53 activation. To further elucidate the pathways involved in the proliferation control of tetraploid cells, we knocked down specific kinases that had been previously linked to the cell cycle arrest and p53 phosphorylation. Our results suggest that the checkpoint kinase ATM phosphorylates p53 in tetraploid cells after abnormal mitosis and thus contributes to proliferation control of human aberrantly arising tetraploids.

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Language(s): eng - English
 Dates: 2013-08
 Publication Status: Issued
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000321950100006
DOI: 10.1007/s00412-013-0414-0
 Degree: -

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Title: CHROMOSOMA
Source Genre: Journal
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Publ. Info: 233 SPRING ST, NEW YORK, NY 10013 USA : SPRINGER
Pages: - Volume / Issue: 122 (4) Sequence Number: - Start / End Page: 305 - 318 Identifier: ISSN: 0009-5915