NF-?B induction of the SUMO protease SENP2: A negative feedback loop to attenuate cell survival response to genotoxic stress.

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

SUBMITTER: Lee MH 

PROVIDER: S-EPMC3172129 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature