Hypersensitivity to DNA damage in antephase as a safeguard for genome stability

Femke M. Feringa, Lenno Krenning, André Koch, Jeroen van den Berg, Bram van den Broek, Kees Jalink and René H. Medema ()
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Femke M. Feringa: The Netherlands Cancer Institute
Lenno Krenning: The Netherlands Cancer Institute
André Koch: The Netherlands Cancer Institute
Jeroen van den Berg: The Netherlands Cancer Institute
Bram van den Broek: The Netherlands Cancer Institute
Kees Jalink: The Netherlands Cancer Institute
René H. Medema: The Netherlands Cancer Institute

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract Activation of the DNA-damage response can lead to the induction of an arrest at various stages in the cell cycle. These arrests are reversible in nature, unless the damage is too excessive. Here we find that checkpoint reversibility is lost in cells that are in very late G2, but not yet fully committed to enter mitosis (antephase). We show that antephase cells exit the cell cycle and enter senescence at levels of DNA damage that induce a reversible arrest in early G2. We show that checkpoint reversibility critically depends on the presence of the APC/C inhibitor Emi1, which is degraded just before mitosis. Importantly, ablation of the cell cycle withdrawal mechanism in antephase promotes cell division in the presence of broken chromosomes. Thus, our data uncover a novel, but irreversible, DNA-damage response in antephase that is required to prevent the propagation of DNA damage during cell division.

Date: 2016
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DOI: 10.1038/ncomms12618

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