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Induction of a pro‐apoptotic ATM–NF‐κB pathway and its repression by ATR in response to replication stress
Author(s) -
Wu ZhaoHui,
Miyamoto Shigeki
Publication year - 2008
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2008.127
Subject(s) - biology , psychological repression , apoptosis , microbiology and biotechnology , replication (statistics) , nfkb1 , nf κb , fight or flight response , genetics , virology , gene , transcription factor , gene expression
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.