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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Dipak Maskey & Shida Yousefi & Inès Schmid & Inti Zlobec & Aurel Perren & Robert Friis & Hans-Uwe Simon, 2013. "ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy," Nature Communications, Nature, vol. 4(1), pages 1-14, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3130
    DOI: 10.1038/ncomms3130
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    Cited by:

    1. Ourania Galanopoulou & Evangelia C. Tachmatzidi & Elena Deligianni & Dimitris Botskaris & Kostas C. Nikolaou & Sofia Gargani & Yannis Dalezios & Georges Chalepakis & Iannis Talianidis, 2024. "Endonucleosis mediates internalization of cytoplasm into the nucleus," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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