Persistent telomere damage induces bypass of mitosis and tetraploidy.
Persistent telomere damage induces bypass of mitosis and tetraploidy.
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DOI：
10.1016/j.cell.2010.01.031
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发表时间：
2010-04-02
期刊：
影响因子：
64.5
通讯作者：
de Lange T
中科院分区：
文献类型：
--
作者：
Davoli T;Denchi EL;de Lange T
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 by-pass 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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