ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response

P. Pawlikowska, I. Leray, B. De Laval, S. Guihard, R. Kumar, F. Rosselli, F. Porteu

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

The early-response gene product IEX-1 (also known as IER3) was recently found to interact with the anti-apoptotic Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1). In this study we show that this interaction specifically and timely controls the accumulation of Mcl-1 in the nucleus in response to DNA damage. The IEX-1 protein is rapidly induced by γ-irradiation, genotoxic agents or replication inhibitors, in a way dependent on ataxia telangiectasia mutated (ATM) activity and is necessary for Mcl-1 nuclear translocation. Conversely, IEX-1 protein proteasomal degradation triggers the return of Mcl-1 to the cytosol. IEX-1 and Mcl-1 are integral components of the DNA damage response. Loss of IEX-1 or Mcl-1 leads to genomic instability and increased sensitivity to genotoxic and replicative stresses. The two proteins cooperate to maintain Chk1 activation and G2 checkpoint arrest. Mcl-1 nuclear translocation may foster checkpoint and improve the tumor resistance to DNA damage-based cancer therapies. Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy.

Original languageEnglish (US)
Pages (from-to)1739-1750
Number of pages12
JournalCell Death and Differentiation
Volume17
Issue number11
DOIs
StatePublished - Nov 2010

Keywords

  • DNA damage
  • IEX-1
  • Mcl-1
  • apoptosis
  • checkpoint

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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