title: ATM regulates NF-κB-dependent immediate-early genes via RelA Ser 276 phosphorylation coupled to CDK9 promoter recruitment.
abstract: Ataxia-telangiectasia mutated (ATM), a member of the phosphatidylinositol 3 kinase-like kinase family, is a master regulator of the double strand DNA break-repair pathway after genotoxic stress. Here, we found ATM serves as an essential regulator of TNF-induced NF-kB pathway. We observed that TNF exposure of cells rapidly induced DNA double strand breaks and activates ATM. TNF-induced ROS promote nuclear IKKγ association with ubiquitin and its complex formation with ATM for nuclear export. Activated cytoplasmic ATM is involved in the selective recruitment of the E3-ubiquitin ligase β-TrCP to phospho-IκBα proteosomal degradation. Importantly, ATM binds and activates the catalytic subunit of protein kinase A (PKAc), ribosmal S6 kinase that controls RelA Ser 276 phosphorylation. In ATM knockdown cells, TNF-induced RelA Ser 276 phosphorylation is significantly decreased. We further observed decreased binding and recruitment of the transcriptional elongation complex containing cyclin dependent kinase-9 (CDK9; a kinase necessary for triggering transcriptional elongation) to promoters of NF-κB-dependent immediate-early cytokine genes, in ATM knockdown cells. We conclude that ATM is a nuclear damage-response signal modulator of TNF-induced NF-κB activation that plays a key scaffolding role in IκBα degradation and RelA Ser 276 phosphorylation. Our study provides a mechanistic explanation of decreased innate immune response associated with A-T mutation.
authors: Department of Internal Medicine, University of Texas Medical Branch (UTMB), 301 University Blvd, Galveston, TX 77555 USA Department of Biochemistry and Molecular Biology, UTMB, Galveston, TX 77555, USA.
authors: Ling
authors: L
authors: Fang
authors: Department of Internal Medicine, University of Texas Medical Branch (UTMB), 301 University Blvd, Galveston, TX 77555 USA Sealy Center for Molecular Medicine, UTMB, 301 University Blvd, Galveston, TX 77555, USA Institute for Translational Sciences, UTMB, 301 University Blvd, Galveston, TX 77555, USA.
authors: Sanjeev
authors: S
authors: Choudhary
authors: Department of Internal Medicine, University of Texas Medical Branch (UTMB), 301 University Blvd, Galveston, TX 77555 USA Sealy Center for Molecular Medicine, UTMB, 301 University Blvd, Galveston, TX 77555, USA Institute for Translational Sciences, UTMB, 301 University Blvd, Galveston, TX 77555, USA.
authors: Yingxin
authors: Y
authors: Zhao
authors: Department of Internal Medicine, University of Texas Medical Branch (UTMB), 301 University Blvd, Galveston, TX 77555 USA.
authors: Chukwudi B
authors: CB
authors: Edeh
authors: Department of Radiation Oncology, Houston Methodist Research Institute, Weill Cornell University, Houston, TX 77030, USA.
authors: Chunying
authors: C
authors: Yang
authors: Sealy Center for Molecular Medicine, UTMB, 301 University Blvd, Galveston, TX 77555, USA Department of Microbiology and Immunology, UTMB, 301 University Blvd, Galveston, TX 77555, USA.
authors: Istvan
authors: I
authors: Boldogh
authors: Department of Internal Medicine, University of Texas Medical Branch (UTMB), 301 University Blvd, Galveston, TX 77555 USA Sealy Center for Molecular Medicine, UTMB, 301 University Blvd, Galveston, TX 77555, USA Institute for Translational Sciences, UTMB, 301 University Blvd, Galveston, TX 77555, USA arbrasie@utmb.edu.
authors: Allan R
authors: AR
authors: Brasier
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012694:Serine / Q000378:metabolism; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D044844:beta-Transducin Repeat-Containing Proteins; D000072000:NF-KappaB Inhibitor alpha; D012694:Serine; D064007:Ataxia Telangiectasia Mutated Proteins; D051550:I-kappa B Kinase; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; D042863:Cyclin-Dependent Kinase 9