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

Zhao-Hui Wu1, Shigeki Miyamoto

  • 1Department of Pharmacology, University of Wisconsin, Madison, WI 53706, USA.

The EMBO Journal
|June 28, 2008
PubMed

Insights

Replication stress and DNA double-strand break inducers activate NF-kappaB signaling. ATR antagonizes this pathway, leading to opposite outcomes in cell death responses.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Genetics

Background:

  • Nuclear factor-kappa B (NF-kappaB) is crucial for cellular responses to DNA damage.
  • ATM (ataxia telangiectasia mutated) kinase mediates NF-kappaB activation via NEMO (NF-kappaB essential modulator) phosphorylation following DNA double-strand breaks (DSBs).

Purpose of the Study:

  • To investigate the role of ATR (ATM- and Rad3-related) in NF-kappaB activation during replication stress.
  • To elucidate the interplay between ATR, ATM, and NEMO in regulating NF-kappaB-dependent apoptosis.

Main Methods:

  • Utilized hydroxyurea (HU) and aphidicolin as replication stress inducers.
  • Employed RNA interference and overexpression to modulate ATR levels.
  • Performed chromatin immunoprecipitation and apoptosis gene expression analysis.

Main Results:

  • Replication stress inducers activate the ATM-dependent NF-kappaB pathway.
  • ATR interacts with NEMO but inhibits NF-kappaB activation, antagonizing ATM.
  • ATR modulates ATM-NEMO association and NF-kappaB activation in response to HU.
  • Replication stress and DSB inducers induce opposing NF-kappaB-dependent apoptotic outcomes.

Conclusions:

  • ATR acts as a negative regulator of NF-kappaB during replication stress, partly by competing with ATM for NEMO binding.
  • The study reveals a conserved NF-kappaB activation pathway with divergent biologic consequences depending on the type of DNA damage.
  • ATR's antagonism of ATM function has significant implications for understanding cellular responses to genotoxic stress.

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