Journal
CELL RESEARCH
Volume 21, Issue 1, Pages 116-130Publisher
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2010.179
Keywords
NF-kappa B; DNA damage; NEMO; ATM; SUMO; DNA damage response; IKK
Categories
Funding
- NATIONAL CANCER INSTITUTE [R01CA077474] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM083681] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA077474] Funding Source: Medline
- NIGMS NIH HHS [R01 GM083681] Funding Source: Medline
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A large body of literature describes elaborate NF-kappa B signaling networks induced by inflammatory and immune signals. Decades of research has revealed that transcriptionally functional NF-kappa B dimers are activated by two major pathways, canonical and non-canonical. Both pathways involve the release of NF-kappa B dimers from inactive cytoplasmic complexes to cause their nuclear translocation to modulate gene expression programs and biological responses. NF-kappa B 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-kappa B essential modulator (NEMO) in the nucleus of a genotoxin-exposed cell. Recent evidence also suggests that this nuclear-initiated NF-kappa B 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.
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