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

25Citations
Citations of this article
31Readers
Mendeley users who have this article in their library.

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. © 2014 The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Cite

CITATION STYLE

APA

Fang, L., Choudhary, S., Zhao, Y., Edeh, C. B., Yang, C., Boldogh, I., & Brasier, A. R. (2014). ATM regulates NF-κB-dependent immediate-early genes via RelA ser 276 phosphorylation coupled to CDK9 promoter recruitment. Nucleic Acids Research, 42(13), 8416–8432. https://doi.org/10.1093/nar/gku529

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free