ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy

Dipak Maskey, Shida Yousefi, Inès Schmid, Inti Zlobec, Aurel Perren, Robert Friis and Hans-Uwe Simon ()
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Dipak Maskey: Institute of Pharmacology, University of Bern
Shida Yousefi: Institute of Pharmacology, University of Bern
Inès Schmid: Institute of Pharmacology, University of Bern
Inti Zlobec: Institute of Pathology, University of Bern
Aurel Perren: Institute of Pathology, University of Bern
Robert Friis: Institute of Pharmacology, University of Bern
Hans-Uwe Simon: Institute of Pharmacology, University of Bern

Nature Communications, 2013, vol. 4, issue 1, 1-14

Abstract: Abstract Anticancer drug therapy activates both molecular cell death and autophagy pathways. Here we show that even sublethal concentrations of DNA-damaging drugs, such as etoposide and cisplatin, induce the expression of autophagy-related protein 5 (ATG5), which is both necessary and sufficient for the subsequent induction of mitotic catastrophe. We demonstrate that ATG5 translocates to the nucleus, where it physically interacts with survivin in response to DNA-damaging agents both in vitro and in carcinoma tissues obtained from patients who had undergone radiotherapy and/or chemotherapy. As a consequence, elements of the chromosomal passenger complex are displaced during mitosis, resulting in chromosome misalignment and segregation defects. Pharmacological inhibition of autophagy does not prevent ATG5-dependent mitotic catastrophe, but shifts the balance to an early caspase-dependent cell death. Our data suggest a dual role for ATG5 in response to drug-induced DNA damage, where it acts in two signalling pathways in two distinct cellular compartments, the cytosol and the nucleus.

Date: 2013
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DOI: 10.1038/ncomms3130

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