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Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia
PLoS One
  • Jean-Luc Perfettini, Université Paris
  • Roberta Nardacci, National Institute for Infectious Diseases
  • Mehdi Bourouba, Institut Gustave Roussy
  • Frederic Subra, Ecole Normale Supe´rieure de Cachan
  • Laurent Gros, Ecole Normale Supe´rieure de Cachan
  • Claire Séror, Institut Gustave Roussy
  • Gwenola Manic, Institut Gustave Roussy
  • Filippo Rosselli, Institut Gustave Roussy
  • Alessandra Amendola, National Institute for Infectious Diseases
  • Peggy Masdehors, Institut Pasteur
  • Luciana Chessa, University of Rome
  • Giuseppe Novelli, University of Rome
  • David M. Ojcius, University of California, Merced
  • Jan Konrad Siwicki, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
  • Magdalena Chechlinska, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
  • Christian Auclair, Ecole Normale Supe´rieure de Cachan
  • Jose R. Regueiro, Universidad Complutense
  • Hughes de Thé, Universite de Paris
  • Marie-Lise Gougeon, Institut Pasteur
  • Mauro Piacentini, National Institute for Infectious Diseases
  • Guido Kroemer, Institut Gustave Roussy
ORCiD
David M. Ojcius: 0000-0003-1461-4495
Document Type
Article
DOI
10.1371/journal.pone.0002458
Publication Date
6-18-2008
Abstract
DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Knockdown of ATM or of its obligate activating factor NBS1 (Nijmegen breakage syndrome 1 protein), as well as pharmacological inhibition of ATM with KU-55933, inhibited H2AX phosphorylation and prevented Env-elicited syncytia from undergoing apoptosis. ATM was found indispensable for the activation of MAP kinase p38, which catalyzes the activating phosphorylation of p53 on serine 46, thereby causing p53 dependent apoptosis. Both wild type HIV-1 and an HIV-1 mutant lacking integrase activity induced syncytial apoptosis, which could be suppressed by inhibiting ATM. HIV-1-infected T lymphoblasts from patients with inactivating ATM or NBS1 mutations also exhibited reduced syncytial apoptosis. Altogether these results indicate that apoptosis induced by a fusogenic HIV-1 Env follows a pro-apoptotic pathway involving the sequential activation of ATM, p38MAPK and p53.
Comments
Article e2458
Citation Information
Jean-Luc Perfettini, Roberta Nardacci, Mehdi Bourouba, Frederic Subra, et al.. "Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia" PLoS One Vol. 3 Iss. 6 (2008) p. 1 - 12 ISSN: 1932-6203
Available at: http://works.bepress.com/david-ojcius/77/