title: NF-κB induction of the SUMO protease SENP2: A negative feedback loop to attenuate cell survival response to genotoxic stress.
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.
authors.affiliation: McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, 6159 Wisconsin Institute for Medical Research, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Moon Hee
authors.initials: MH
authors.lastname: Lee
authors.forename: Angela M
authors.initials: AM
authors.lastname: Mabb
authors.forename: Grace B
authors.initials: GB
authors.lastname: Gill
authors.forename: Edward T H
authors.initials: ET
authors.lastname: Yeh
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008745:Methylation; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D058207:Sumoylation; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; C491731:IKBKG protein, human; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase; D003546:Cysteine Endopeptidases; C501833:SENP2 protein, human