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Nat Commun. 2019 Sep 17;10(1):4224. doi: 10.1038/s41467-019-12255-w.

Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection.

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Children's Medical Research Institute, University of Sydney, Westmead, NSW, 2145, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
Department of Medical Biology, The University of Melbourne, Parkville, VIC, 3052, Australia.
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198, Gif-sur-Yvette cedex, France.
LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS/UPS, Toulouse, France.
The Salk Institute for Biological Studies, Molecular and Cell Biology Department, La Jolla, CA, 92037, USA.
Department of Gene Mechanisms, Graduate School of Biostudies/The Hakubi Center for Advanced Research, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
Children's Medical Research Institute, University of Sydney, Westmead, NSW, 2145, Australia.


Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death in replication stressed cells results in distinct cellular outcomes depending upon how cell death is averted. These data demonstrate how replication stress-induced mitotic catastrophe signals cell death with implications for cancer treatment and cancer genome evolution.

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