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Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli

Zhao-Hui Wu1, Yuling Shi, Randal S Tibbetts

  • 1Department of Pharmacology, University of Wisconsin-Madison, 301 SMI, 1300 University Avenue, Madison, WI 53706, USA.

Science (New York, N.Y.)
|February 25, 2006
PubMed

Insights

The NF-kappaB essential modulator (NEMO) protein links ATM and IKK signaling pathways. This interaction activates NF-kappaB in response to DNA damage, influencing cell death pathways.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • DNA Damage Response

Background:

  • The transcription factor NF-kappaB plays a crucial role in modulating apoptotic responses to genotoxic stress.
  • NF-kappaB signaling is tightly regulated by the IkappaB kinase (IKK) complex, which includes the NF-kappaB essential modulator (NEMO) subunit.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which genotoxic stress activates NF-kappaB.
  • To investigate the role of ataxia telangiectasia mutated (ATM) kinase in the regulation of NEMO and NF-kappaB activation.

Main Methods:

  • Co-immunoprecipitation assays to study protein-protein interactions between ATM, NEMO, and IKK.
  • Western blotting to detect phosphorylation and ubiquitination of NEMO.
  • Immunofluorescence microscopy to track the subcellular localization of ATM and NEMO.

Main Results:

  • Activated ATM kinase associates with NEMO following DNA double-strand breaks.
  • ATM phosphorylates serine-85 of NEMO, promoting its nuclear export.
  • NEMO facilitates the cytoplasmic translocation and activation of IKK by ATM, involving the ELKS protein.

Conclusions:

  • Regulated nuclear shuttling of NEMO is a key event linking ATM and IKK signaling pathways.
  • This NEMO-dependent mechanism activates NF-kappaB in response to genotoxic signals, impacting cellular fate.
  • The findings provide new insights into the intricate network of DNA damage response and NF-kappaB activation.

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