Abstract
The transcription factor NF-kappaB is critical for setting the cellular sensitivities to apoptotic stimuli, including DNA damaging anticancer agents. Central to NF-kappaB signaling pathways is NEMO/IKKgamma, the regulatory subunit of the cytoplasmic IkappaB kinase (IKK) complex. While NF-kappaB activation by genotoxic stress provides an attractive paradigm for nuclear-to-cytoplasmic signaling pathways, the mechanism by which nuclear DNA damage modulates NEMO to activate cytoplasmic IKK remains unknown. Here, we show that genotoxic stress causes nuclear localization of IKK-unbound NEMO via site-specific SUMO-1 attachment. Surprisingly, this sumoylation step is ATM-independent, but nuclear localization allows subsequent ATM-dependent ubiquitylation of NEMO to ultimately activate IKK in the cytoplasm. Thus, genotoxic stress induces two independent signaling pathways, SUMO-1 modification and ATM activation, which work in concert to sequentially cause nuclear targeting and ubiquitylation of free NEMO to permit the NF-kappaB survival pathway. These SUMO and ubiquitin modification pathways may serve as anticancer drug targets.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus / genetics
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Amino Acid Sequence / genetics
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / genetics
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Ataxia Telangiectasia Mutated Proteins
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COS Cells
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Cell Cycle Proteins
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Cytoplasm / genetics
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Cytoplasm / metabolism
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DNA Damage / genetics*
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DNA-Binding Proteins
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Humans
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I-kappa B Kinase
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Lysine / metabolism
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Mice
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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SUMO-1 Protein / genetics
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SUMO-1 Protein / metabolism*
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Signal Transduction / genetics
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Tumor Suppressor Proteins
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Ubiquitin / genetics
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Ubiquitin / metabolism*
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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DNA-Binding Proteins
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NF-kappa B
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SUMO-1 Protein
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Tumor Suppressor Proteins
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Ubiquitin
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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CHUK protein, human
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Chuk protein, mouse
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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Ikbkb protein, mouse
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Ikbke protein, mouse
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Lysine