Activation of NF-κB, pivotal for immunity and oncogenesis, is tightly controlled by multiple feedback mechanisms. In response to DNA damage, SUMOylation of NEMO (NF-κB essential modulator) is critical for NF-κB activation; however, the SUMO proteases and feedback mechanisms involved remain unknown. Here we show that among the six known Sentrin/SUMO-specific proteases (SENPs), only SENP2 can efficiently associate with NEMO, deSUMOylate NEMO, and inhibit NF-κB activation induced by DNA damage. We further show that NF-κB induces SENP2 (and SENP1) transcription selectively in response to genotoxic stimuli, which involves ataxia telangiectasia mutated (ATM)-dependent histone methylation of SENP2 promoter κB regions and NF-κB recruitment. SENP2 null cells display biphasic NEMO SUMOylation and activation of IKK and NF-κB, and higher resistance to DNA damage-induced cell death. Our study establishes a self-attenuating feedback mechanism selective to DNA damage-induced signaling to limit NF-κB-dependent cell survival responses.
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