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

30 Scopus citations

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

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'ATM regulates NF-κB-dependent immediate-early genes via RelA ser 276 phosphorylation coupled to CDK9 promoter recruitment'. Together they form a unique fingerprint.

  • Cite this