Persistent telomere damage induces bypass of mitosis and tetraploidy.
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.
Davoli
Teresa
T
Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Denchi
Eros Lazzerini
EL
de Lange
Titia
T
D064173:Anaphase-Promoting Complex-Cyclosome; D000782:Aneuploidy; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004249:DNA Damage; D004622:Embryo, Mammalian / Q000166:cytology; D006801:Humans; D051379:Mice; D008938:Mitosis; D009369:Neoplasms / Q000235:genetics*; D011003:Ploidies; D016615:Telomere / Q000235:genetics*; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
D015820:Cadherins; D018797:Cell Cycle Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome