Nuclear initiated NF-κB signaling: NEMO and ATM take center stage

Cell Res. 2011 Jan;21(1):116-30. doi: 10.1038/cr.2010.179. Epub 2010 Dec 28.


A large body of literature describes elaborate NF-κB signaling networks induced by inflammatory and immune signals. Decades of research has revealed that transcriptionally functional NF-κB dimers are activated by two major pathways, canonical and non-canonical. Both pathways involve the release of NF-κB dimers from inactive cytoplasmic complexes to cause their nuclear translocation to modulate gene expression programs and biological responses. NF-κB is also responsive to genotoxic agents; however, signal communication networks that are initiated in the nucleus following DNA damage induction are less defined. Evidence in the literature supports the presence of such signaling pathways induced by multiple distinct genotoxic agents, resulting in the activation of cytoplasmic IKK complex. An example is a pathway that involves the DNA damage-responsive kinase ataxia telangiectasia mutated (ATM) and a series of post-translational modifications of NF-κB essential modulator (NEMO) in the nucleus of a genotoxin-exposed cell. Recent evidence also suggests that this nuclear-initiated NF-κB signaling pathway plays significant physiological and pathological roles, particularly in lymphocyte development and human cancer progression. This review will summarize these new developments, while identifying significant unanswered questions and providing new hypotheses that may be addressed in future studies.

Publication types

  • Review

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism*
  • Cell Cycle Proteins / physiology
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology
  • Humans
  • I-kappa B Kinase / metabolism*
  • I-kappa B Kinase / physiology
  • NF-kappa B / metabolism*
  • NF-kappa B / physiology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism*
  • Tumor Suppressor Proteins / physiology


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • IKBKG protein, human
  • NF-kappa B
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • I-kappa B Kinase