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

Maskey, Dipak; Yousefi, Shida; Schmid, Ines; Zlobec, Inti; Perren, Aurel; Friis, Robert; Simon, Hans-Uwe (2013). ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy. Nature communications, 4, p. 2130. Nature Publishing Group 10.1038/ncomms3130

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Maskey, Dipak; Yousefi, Shida; Schmid, Ines; Zlobec, Inti; Perren, Aurel; Friis, Robert and Simon, Hans-Uwe

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Anita Dähler

Date Deposited:

11 Mar 2014 10:38

Last Modified:

26 Jun 2016 01:46

Publisher DOI:

10.1038/ncomms3130

PubMed ID:

23945651

BORIS DOI:

10.7892/boris.41904

URI:

https://boris.unibe.ch/id/eprint/41904

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