A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation

Hinz, Michael, Stilmann, Michael, Arslan, Seda Çöl, Khanna, Kum Kum, Dittmar, Gunnar and Scheidereit, Claus (2010) A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation. Molecular Cell, 40 1: 63-74. doi:10.1016/j.molcel.2010.09.008

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Author Hinz, Michael
Stilmann, Michael
Arslan, Seda Çöl
Khanna, Kum Kum
Dittmar, Gunnar
Scheidereit, Claus
Title A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-κB activation
Journal name Molecular Cell   Check publisher's open access policy
ISSN 1097-2765
1097-4164
Publication date 2010-10-08
Sub-type Article (original research)
DOI 10.1016/j.molcel.2010.09.008
Volume 40
Issue 1
Start page 63
End page 74
Total pages 12
Place of publication Cambridge, MA, U.S.A.
Publisher Cell Press
Collection year 2011
Language eng
Abstract As part of the genotoxic stress response, cells activate the transcription factor NF-κB. The DNA strand break sensor poly(ADP-ribose)-polymerase-1 (PARP-1) and the kinase ataxia telangiectasia mutated (ATM) act as proximal signal mediators. PARP-1 assembles a nucleoplasmic signalosome, which triggers PIASy-mediated IKKγ SUMOylation. ATM-dependent IKKγ phosphorylation and subsequent ubiquitination were implicated to activate the cytoplasmic IκB kinase (IKK) complex by unknown mechanisms. We show that activated ATM translocates in a calcium-dependent manner to cytosol and membrane fractions. Through a TRAF-binding motif, ATM activates TRAF6, resulting in Ubc13-mediated K63-linked polyubiquitin synthesis and cIAP1 recruitment. The ATM-TRAF6-cIAP1 module stimulates TAB2-dependent TAK1 phosphorylation. Both nuclear PARP-1- and cytoplasmic ATM-driven signaling branches converge at the IKK complex to catalyze monoubiquitination of IKKγ at K285. Our data indicate that exported SUMOylated IKKγ acts as a substrate. IKKγ monoubiquitination is a prerequisite for genotoxic IKK and NF-κB activation, but also promotes cytokine signaling. Copyright © 2011 Elsevier B.V. All rights reserved.
Keyword Double-strang breaks
Genotoxic stress
Polyubiquitin chains
Molecular-mechanism
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
 
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Created: Fri, 01 Apr 2011, 08:53:11 EST by Debbie Banks on behalf of School of Medicine