| Persistent telomere damage induces bypass of mitosis and tetraploidy. | |
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MedLine Citation:
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PMID: 20371347 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tetraploidization has been proposed as an intermediate step toward aneuploidy in human cancer but a general mechanism for the induction of tetraploidy during tumorigenesis is lacking. We report that tetraploidization occurs in p53-deficient cells experiencing a prolonged DNA damage signal due to persistent telomere dysfunction. Live-cell imaging revealed that these cells have an extended G2 due to ATM/ATR- and Chk1/Chk2-mediated inhibition of Cdk1/CyclinB and eventually bypass mitosis. Despite their lack of mitosis, the cells showed APC/Cdh1-dependent degradation of the replication inhibitor geminin, followed by accumulation of Cdt1, which is required for origin licensing. Cells then entered a second S phase resulting in whole-genome reduplication and tetraploidy. Upon restoration of telomere protection, these tetraploid cells resumed cell division cycles and proliferated. These observations suggest a general mechanism for the induction of tetraploidization in the early stages of tumorigenesis when telomere dysfunction can result from excessive telomere shortening. |
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Authors:
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Teresa Davoli; Eros Lazzerini Denchi; Titia de Lange |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cell Volume: 141 ISSN: 1097-4172 ISO Abbreviation: Cell Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2010-04-07 Completed Date: 2010-04-22 Revised Date: 2011-07-27 |
Medline Journal Info:
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Nlm Unique ID: 0413066 Medline TA: Cell Country: United States |
Other Details:
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Languages: eng Pagination: 81-93 Citation Subset: IM |
Copyright Information:
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Copyright 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aneuploidy Animals Cadherins / metabolism Cell Cycle Proteins / metabolism Cell Line DNA Damage Embryo, Mammalian / cytology Humans Mice Mitosis* Neoplasms / genetics* Ploidies* Telomere / genetics* Ubiquitin-Protein Ligase Complexes / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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DP1 OD000379-05/OD/NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cadherins; 0/Cell Cycle Proteins; EC 6.3.2.19/Ubiquitin-Protein Ligase Complexes; EC 6.3.2.19/anaphase-promoting complex |
| Comments/Corrections | |
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