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A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation

Michael Hinz1, Michael Stilmann, Seda Çöl Arslan

  • 1Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.

Molecular Cell
|October 12, 2010
PubMed

Insights

Genotoxic stress activates nuclear poly(ADP-ribose)-polymerase-1 (PARP-1) and cytoplasmic ataxia telangiectasia mutated (ATM) signaling. These pathways converge to monoubiquitinate IKKγ, a crucial step for activating the IκB kinase (IKK) and NF-κB pathways.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Signaling Pathways

Background:

  • The genotoxic stress response involves the activation of transcription factor NF-κB.
  • Poly(ADP-ribose)-polymerase-1 (PARP-1) and ataxia telangiectasia mutated (ATM) are key mediators in DNA damage signaling.
  • The precise mechanisms of IκB kinase (IKK) complex activation downstream of ATM remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which ATM activates the IKK complex during genotoxic stress.
  • To identify the convergence point of PARP-1 and ATM signaling pathways in NF-κB activation.
  • To characterize the role of IKKγ modifications in genotoxic stress response.

Main Methods:

  • Investigated the subcellular localization of ATM upon genotoxic stress.
  • Utilized biochemical assays to study protein-protein interactions and modifications (SUMOylation, phosphorylation, ubiquitination).
  • Employed molecular biology techniques to analyze signaling cascades involving TRAF6, cIAP1, TAK1, and IKK complex.

Main Results:

  • Activated ATM translocates to the cytosol and membrane fractions in a calcium-dependent manner.
  • ATM activates TRAF6, leading to K63-linked polyubiquitin synthesis and subsequent TAK1 phosphorylation via the ATM-TRAF6-cIAP1 module.
  • Both nuclear PARP-1 and cytoplasmic ATM signaling converge on the IKK complex, catalyzing IKKγ monoubiquitination at K285, which is essential for IKK and NF-κB activation.

Conclusions:

  • Genotoxic stress response involves coordinated nuclear and cytoplasmic signaling pathways.
  • IKKγ monoubiquitination, downstream of PARP-1 and ATM, is a critical prerequisite for IKK and NF-κB activation.
  • The elucidated pathway also plays a role in promoting cytokine signaling.

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