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

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Ling Fang1, Sanjeev Choudhary2, Yingxin Zhao2

  • 1Department 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.

Nucleic Acids Research
|June 25, 2014
PubMed

Insights

Ataxia-telangiectasia mutated (ATM) regulates the TNF-induced NF-kB pathway by modulating DNA damage response, impacting innate immunity. This study reveals ATM

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Immunology

Background:

  • Ataxia-telangiectasia mutated (ATM) is crucial for DNA double-strand break repair.
  • The NF-kB pathway is central to inflammatory and immune responses.
  • Tumor Necrosis Factor (TNF) activates signaling cascades, including NF-kB.

Purpose of the Study:

  • To investigate the role of ATM in TNF-induced NF-kB activation.
  • To elucidate the molecular mechanisms by which ATM modulates NF-kB signaling.
  • To understand the implications of ATM function in innate immunity.

Main Methods:

  • Cellular assays to assess DNA double-strand breaks and ATM activation upon TNF exposure.
  • Analysis of protein-protein interactions and subcellular localization (e.g., nuclear export).
  • Western blotting and knockdown studies to evaluate protein phosphorylation (e.g., RelA Ser 276) and gene expression.

Main Results:

  • TNF exposure induces DNA double-strand breaks, activating ATM.
  • ATM facilitates IKKγ ubiquitination, nuclear export, and subsequent IκBα degradation via β-TrCP.
  • ATM activation leads to PKAc-mediated RelA Ser 276 phosphorylation and enhanced recruitment of the CDK9 complex to NF-kB target gene promoters.

Conclusions:

  • ATM acts as a critical modulator of TNF-induced NF-kB activation, bridging DNA damage response with immune signaling.
  • ATM plays a scaffolding role in IκBα degradation and RelA phosphorylation, essential for cytokine gene transcription.
  • Dysregulation of ATM may underlie the impaired innate immune responses observed in Ataxia-Telangiectasia mutations.

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