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A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced IkappaB kinase activation

Michael Stilmann1, Michael Hinz, Seda Cöl Arslan

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

Molecular Cell
|November 18, 2009
PubMed

Insights

Poly(ADP-ribose)-polymerase-1 (PARP-1) senses DNA breaks and initiates IKKgamma SUMOylation, activating IKK and NF-kappaB. This pathway enhances cellular resistance to apoptosis following genotoxic stress.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Genetics

Background:

  • Genotoxic stresses activate IkappaB kinases (IKKs) and NF-kappaB to regulate apoptosis.
  • Nuclear IKKgamma (NEMO) is SUMOylated and phosphorylated by PIASy and ATM, respectively, activating cytoplasmic IKKs.
  • The nuclear signals initiating IKKgamma recruitment and activation remain unclear.

Purpose of the Study:

  • To identify the nuclear signals and scaffold structures responsible for initiating IKKgamma recruitment and activation upon genotoxic stress.
  • To elucidate the role of poly(ADP-ribose)-polymerase-1 (PARP-1) in the DNA damage response pathway involving IKKgamma.

Main Methods:

  • Investigated protein-protein interactions and complex formation using biochemical assays.
  • Utilized poly(ADP-ribose) (PAR) synthesis and PAR binding motifs (PARBM) in signalosome assembly.
  • Assessed the requirement of activated PARP-1 and PIASy PARBM for IKKgamma SUMOylation and subsequent NF-kappaB activation.

Main Results:

  • Identified PARP-1 as a DNA-proximal regulator that senses DNA strand breaks.
  • Demonstrated that PARP-1, via PAR synthesis, dynamically assembles IKKgamma, PIASy, and ATM.
  • Showed that activated PARP-1 and a PIASy PARBM are essential for IKKgamma SUMOylation, leading to IKK/NF-kappaB activation.

Conclusions:

  • PARP-1 acts as a crucial scaffold, initiating the SUMOylation of IKKgamma (NEMO) in response to DNA damage.
  • This PARP-1-mediated pathway activates the IKK/NF-kappaB signaling cascade, conferring resistance to apoptosis.
  • The findings reveal a novel mechanism linking DNA damage sensing to the NF-kappaB pathway.

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