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

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 SUMO proteases and feedback mechanisms involved remain unknown. Here we show that among the six known SENPs (Sentrin/SUMO-specific proteases) 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 ATM (ataxia telangiectasia mutated)-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