ATM regulates NF-κB-dependent immediate-early genes via RelA ser 276 phosphorylation coupled to CDK9 promoter recruitment

Ling Fang, Sanjeev Choudhary, Yingxin Zhao, Chukwudi B. Edeh, Chunying Yang, Istvan Boldogh, Allan R. Brasier

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8416-8432
Number of pages17
JournalNucleic Acids Research
Volume42
Issue number13
DOIs
StatePublished - 2014

Fingerprint

Ataxia Telangiectasia
Immediate-Early Genes
Phosphorylation
Cyclin-Dependent Kinase 9
Double-Stranded DNA Breaks
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
Phosphatidylinositol 3-Kinase
Ribosomal Protein S6 Kinases
Ubiquitin-Protein Ligases
Cell Nucleus Active Transport
NF-kappa B
Ubiquitin
Innate Immunity
DNA Repair
DNA Damage
Phosphotransferases
Cytokines
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

ATM regulates NF-κB-dependent immediate-early genes via RelA ser 276 phosphorylation coupled to CDK9 promoter recruitment. / Fang, Ling; Choudhary, Sanjeev; Zhao, Yingxin; Edeh, Chukwudi B.; Yang, Chunying; Boldogh, Istvan; Brasier, Allan R.

In: Nucleic Acids Research, Vol. 42, No. 13, 2014, p. 8416-8432.

Research output: Contribution to journalArticle

Fang, Ling ; Choudhary, Sanjeev ; Zhao, Yingxin ; Edeh, Chukwudi B. ; Yang, Chunying ; Boldogh, Istvan ; Brasier, Allan R. / ATM regulates NF-κB-dependent immediate-early genes via RelA ser 276 phosphorylation coupled to CDK9 promoter recruitment. In: Nucleic Acids Research. 2014 ; Vol. 42, No. 13. pp. 8416-8432.
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AU - Brasier, Allan R.

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