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

Françoise Porteu (1) , Patrycja Pawlikowska (1) , Isabelle Leray (1) , Bérengère de Laval (1) , Soizic Guihard (1) , Rajiv Kumar (1) , Filippo Rosselli (1)

1 Immunology-Hematology

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). We show here 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 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.

Mots clés: Bcl2-family; Mcl-1; DNA damage response; checkpoint; IEX-1

Françoise Porteu, Patrycja Pawlikowska, Isabelle Leray, Bérengère de Laval, Soizic Guihard, et al.. ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response. Cell Death and Differentiation, 2010, ⟨10.1038/cdd.2010.56⟩. ⟨hal-00535923⟩