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

Mol Cell. 2011 Jul 22;43(2):180-91. doi: 10.1016/j.molcel.2011.06.017.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Survival
  • Cells, Cultured
  • Cysteine Endopeptidases / genetics*
  • Cysteine Endopeptidases / metabolism*
  • DNA Damage
  • DNA-Binding Proteins / metabolism
  • Histones / metabolism
  • Humans
  • I-kappa B Kinase / metabolism
  • Methylation
  • NF-kappa B / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Sumoylation
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Histones
  • IKBKG protein, human
  • NF-kappa B
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases
  • I-kappa B Kinase
  • Cysteine Endopeptidases
  • SENP2 protein, human