NF-κB Induction of the SUMO Protease SENP2: A Negative Feedback Loop to Attenuate Cell Survival Response to Genotoxic Stress

Activation of NF-kappa B, pivotal for immunity and oncogenesis, is tightly controlled by multiple feedback mechanisms. In response to DNA damage, SUMOylation of NEMO (NF-kappa B essential modulator) is critical for NF-kappa B 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-kappa B activation induced by DNA damage. We further show that NF-kappa B induces SENP2 (and SENP1) transcription selectively in response to genotoxic stimuli, which involves ataxia telangiectasia mutated (ATM)-dependent histone methylation of SENP2 promoter kappa B regions and NF-kappa B recruitment. SENP2 null cells display biphasic NEMO SUMOylation and activation of IKK and NF-kappa B, 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-kappa B-dependent cell survival responses.