Induction of a pro-apoptotic ATM-NF-κB pathway and its repression by ATR in response to replication stress

Zhaohui Wu, Shigeki Miyamoto

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The transcription factor NF-κB has critical functions in biologic responses to genotoxic stimuli. Activation of NF-κB in response to DNA double strand break (DSB) inducers can be mediated by ATM (ataxia telangiectasia mutated)-dependent phosphorylation of NEMO (NF-κB essential modulator). Here, we show that the replication stress inducers hydroxyurea (HU) and aphidicolin also activate this ATM-dependent signalling pathway. We further show that ATR (ATM- and Rad3-related) interacts with NEMO but surprisingly does not cause NEMO phosphorylation. Consequently, ATR represses NF-κB activation induced by replication stress. Reduction or increase of ATR expression by RNA interference or overexpression increased or reduced ATM-NEMO association and NF-κB activation induced by HU. Apoptosis gene expression and chromatin immunoprecipitation analyses indicated that HU and the DSB inducer etoposide caused complex patterns of NF-κB-dependent pro- and antiapoptotic gene expression with the overall outcome for the former being pro-apoptotic, whereas the latter antiapoptotic. Thus, replication stress and DSB inducers activate NF-κB through a conserved pathway with opposite biologic outcomes, and ATR antagonizes ATM function at least in part by competing for NEMO association.

Original languageEnglish (US)
Pages (from-to)1963-1973
Number of pages11
JournalEMBO Journal
Volume27
Issue number14
DOIs
StatePublished - Jul 23 2008
Externally publishedYes

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Ataxia Telangiectasia
Automatic teller machines
Modulators
Hydroxyurea
Phosphorylation
Chemical activation
Gene expression
Association reactions
Aphidicolin
Gene Expression
Double-Stranded DNA Breaks
Chromatin Immunoprecipitation
Etoposide
RNA Interference
Chromatin
Transcription Factors
RNA
Apoptosis
DNA

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Induction of a pro-apoptotic ATM-NF-κB pathway and its repression by ATR in response to replication stress. / Wu, Zhaohui; Miyamoto, Shigeki.

In: EMBO Journal, Vol. 27, No. 14, 23.07.2008, p. 1963-1973.

Research output: Contribution to journalArticle

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