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  • The EMBO Journal (2009) 28, 1576 - 1588
  • doi:10.1038/emboj.2009.106

Published online: 23 April 2009

The antiapoptotic protein AAC-11 interacts with and regulates Acinus-mediated DNA fragmentation

Patricia Rigou1,a, Valeria Piddubnyak1,ab, Audrey Faye1,2, Jean-Christophe Rain3, Laurence Michel4, Fabien Calvo1,2 and Jean-Luc Poyet1,2

  1. INSERM UMRS 940, Equipe Avenir, Université Paris 7, Institut de Génétique Moléculaire, Paris, France
  2. c-Dithem, Inserm Consortium for Discovery and Innovation in Therapy and Medicine
  3. Hybrigenics, Paris, France
  4. INSERM U697, Hôpital Saint-Louis, Claude Vellefaux, Paris, France

Correspondence to:

Jean-Luc Poyet, INSERM UMRS 940, Equipe Avenir, Université Paris 7, Institut de Génétique Moléculaire, 27 rue Juliette Dodu, 75010 Paris, France. Tel.: +33 1 42499263; Fax: +33 1 42494838; E-mail: jean-luc.poyet@inserm.fr

aThese authors contributed equally to this work

bPresent address: Unité de Génétique, Papillomavirus et Cancer humain (GPCH), Département Virologie, Institut Pasteur, 25 rue du Dr Roux 75015 Paris, France

Received 13 November 2008; Accepted 23 March 2009

The nuclear factor Acinus has been suggested to mediate apoptotic chromatin condensation after caspase cleavage. However, this role has been challenged by recent observations suggesting a contribution of Acinus in apoptotic internucleosomal DNA cleavage. We report here that AAC-11, a survival protein whose expression prevents apoptosis that occurs on deprivation of growth factors, physiologically binds to Acinus and prevents Acinus-mediated DNA fragmentation. AAC-11 was able to protect Acinus from caspase-3 cleavage in vivo and in vitro, thus interfering with its biological function. Interestingly, AAC-11 depletion markedly increased cellular sensitivity to anticancer drugs, whereas its expression interfered with drug-induced cell death. AAC-11 possesses a leucine-zipper domain that dictates, upon oligomerization, its interaction with Acinus as well as the antiapoptotic effect of AAC-11 on drug-induced cell death. A cell permeable peptide that mimics the leucine-zipper subdomain of AAC-11, thus preventing its oligomerization, inhibited the AAC-11–Acinus complex formation and potentiated drug-mediated apoptosis in cancer cells. Our results, therefore, show that targeting AAC-11 might be a potent strategy for cancer treatment by sensitization of tumour cells to chemotherapeutic drugs.

  • Keywords:

    • AAC-11,
    • Acinus,
    • cell death,
    • DNA fragmentation,
    • peptide