Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy

SummaryTetraploidization 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.PaperFlick To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon belowHelp with MP4 filesOptionsDownload video (51465 K)

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (361 K)Download as PowerPoint slideHighlights► Dysfunctional telomeres can elicit a persistent DNA damage signal ► Persistent DNA damage signaling causes endoreduplication in p53-deficient cells ► Bypass of mitosis, geminin degradation, and Cdt1 re-expression allow a 2nd S phase ► Tetraploidy resulting from this pathway may lead to cancer-associated aneuploidy