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Sci. STKE, 2 December 2003
Vol. 2003, Issue 211, p. tw464
[DOI: 10.1126/stke.2112003tw464]

EDITORS' CHOICE

GENOTOXIC STRESS Sumoylating NEMO

Huang et al. investigated activation of the transcription factor nuclear factor-{kappa}B (NF-{kappa}B) and implicated two distinct signaling pathways in the response to genotoxic stress. NF-{kappa}B, which mediates cellular responses to stress, is sequestered in the cytoplasm through interactions with its inhibitors, I{kappa}Bα and I{kappa}Bβ. Stimulation by proinflammatory cytokines, or other extracellular mediators of stress responses, leads to activation of I{kappa}B kinase (IKK) [composed of two catalytic subunits and the NF-{kappa}B essential modulator (NEMO) regulatory subunit]. IKK activation leads to the proteasomal degradation of I{kappa}B and the release of NF-{kappa}B, which translocates to the nucleus and activates target genes. NF-{kappa}B activation following damage to DNA also depends on modulation of NEMO to activate IKK; however, the mechanisms underlying the nuclear-to-cytoplasmic signaling pathway remain poorly understood. Huang et al. used Western analysis in combination with immunoprecipitation to show that, in mouse 1.3E2 pre-B cells transfected with NEMO, DNA-damaging chemotherapeutic agents induced first NEMO sumoylation and then NEMO ubiquitination. Sumoylation, which was required for DNA damage-dependent activation of IKK and NF-{kappa}B, led to nuclear accumulation of NEMO that was not associated with IKK. Small interfering RNA knockdown of the ataxia telangiectasia mutant (ATM) kinase, a nuclear kinase that has been implicated in DNA-damage pathways, indicated that ATM was required for NEMO ubiquitination but not sumoylation. Experiments in which NF-{kappa}B-I{kappa}Bα and NF-{kappa}B-I{kappa}Bβ were respectively localized to the nucleus and cytoplasm by inhibiting nuclear export indicated that NEMO activation of IKK and NF-{kappa}B following DNA damage occurred in the cytoplasm. Thus, NF-{kappa}B activation in response to genotoxic agents involves ATM-independent NEMO sumoylation, which leads to NEMO's accumulation in the nucleus, followed by ATM-dependent ubiquitination, and finally by IKK activation in the cytoplasm.

T. T. Huang, S. M. Wuerberger-Davis, Z.-H. Wu, S. Miyamoto, Sequential modification of NEMO/IKK{gamma} by SUMO-1 and ubiquitin mediates NF-{kappa}B activation by genotoxic stress. Cell 115, 565-576 (2003). [Online Journal]

Citation: Sumoylating NEMO. Sci. STKE 2003, tw464 (2003).


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