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Sci. Signal., 18 January 2011
Vol. 4, Issue 156, p. pe2
[DOI: 10.1126/scisignal.2001712]

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Signals from the Nucleus: Activation of NF-{kappa}B by Cytosolic ATM in the DNA Damage Response

Kamyar Hadian1 and Daniel Krappmann2*

1 Assay Development and Screening Platform, Helmholtz Zentrum München–German Research Center for Environmental Health, Institute of Toxicology, 85764 Neuherberg, Germany.
2 Department of Cellular Signal Integration, Helmholtz Zentrum München–German Research Center for Environmental Health, Institute of Toxicology, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.

Abstract: In response to genotoxic stress induced by DNA double-stranded breaks (DSBs), the inhibitor of {kappa}B kinase (IKK) to nuclear factor {kappa}B (NF-{kappa}B) pathway is activated, which can promote cancer progression and increase the resistance of cancer cells to ionizing radiation or chemotherapeutic drugs. The kinase ataxia telangiectasia mutated (ATM) has a critical role in the activation of NF-{kappa}B in response to genotoxic stress. Two reports reveal key cytoplasmic functions of ATM in triggering IKK activation upon DNA damage. After induction of DSBs, ATM is exported from the nucleus and stimulates the ubiquitin ligase activity of tumor necrosis factor receptor–associated factor 6 (TRAF6) or X-linked inhibitor of apoptosis protein, which catalyze the auto-polyubiquitylation of TRAF6 and the polyubiquitylation of the IKK adaptor ELKS, respectively. Ubiquitylation promotes the assembly of signalosomes containing the kinase TAK1 (transforming growth factor b–activated kinase 1). These signalosomes are the site of activation of the cytosolic IKK complex, which stimulates NF-{kappa}B–dependent induction of a proliferative and antiapoptotic gene program. These studies show that ATM executes essential functions outside the nucleus in response to DSBs.

* Corresponding author. E-mail, danielkrappmann{at}helmholtz-muenchen.de

Citation: K. Hadian, D. Krappmann, Signals from the Nucleus: Activation of NF-{kappa}B by Cytosolic ATM in the DNA Damage Response. Sci. Signal. 4, pe2 (2011).

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