title: ATG5: a distinct role in the nucleus.
abstract: Both apoptotic and autophagic pathways are activated in cells during anticancer treatment using DNA-damaging agents. Thus, the outcome is balanced between apoptotic cell death and enhanced autophagy, with the possibility of prolonged cell survival. It seems intuitively obvious that this survival mechanism might interfere with the desired tumor cell killing. We addressed this question by tipping the balance in favor of autophagy, using etoposide or cisplatin at low, sublethal doses. Over 4 days, only a little apoptosis was observed, but both drugs sharply increased autophagic flux. Surprisingly, cells underwent a cell cycle arrest at G 2/M, followed later by mitotic catastrophe with formation of multipolar spindles, missegregated chromosomes, or enlarged, irregular, sometimes multiple nuclei. Why? The answer is that even a low level of DNA damage not only upregulates autophagy, but also provokes the recruitment of an autophagy-related protein, ATG5, to the nucleus, where it binds BIRC5/survivin, thereby interfering with correct assembly of the chromosome passenger complex needed for cytokinesis.
authors.affiliation: Institute of Pharmacology; University of Bern; Bern, Switzerland.
authors.forename: Hans-Uwe
authors.initials: HU
authors.lastname: Simon
authors.affiliation: Institute of Pharmacology; University of Bern; Bern, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Friis
mesh_terms: D000818:Animals; D001343:Autophagy; D002467:Cell Nucleus / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008954:Models, Biological; D010588:Phagosomes / Q000378:metabolism
chemical_list: D008869:Microtubule-Associated Proteins
keywords: ATG5; Aurora B; DNA damage; anticancer drugs; apoptosis; autophagy; chromosomal passenger complex; mitotic catastrophe; survivin