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First published online March 18, 2009
doi: 10.1242/10.1242/jcs.043539

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An interaction network of the mammalian COP9 signalosome identifies Dda1 as a core subunit of multiple Cul4-based E3 ligases

Michael Hans Olma^1,*, Marcia Roy^2,*,, Thierry Le Bihan³, Izabela Sumara¹, Sarah Maerki¹, Brett Larsen², Manfredo Quadroni⁴, Matthias Peter^1,, Mike Tyers^2,, and Lionel Pintard^2,5,

¹ Swiss Federal Institute of Technology Zürich (ETH), Institute of Biochemistry, 8093 Zürich, Switzerland
² Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Ontario Toronto, Canada M5G 1X5
³ Centre for Systems Biology at Edinburgh (CSBE), The University of Edinburgh, The Kings Buildings, Mayfield Road, Edinburgh EH9 3JU
⁴ Centre Intégratif de Génomique, plateforme de protéomique, Chemin des Boveresses 155, 1066 Epalinges, Switzerland
⁵ Institut Jacques Monod CNRS, Université Paris Diderot, 5 Rue Thomas Mann, 75205 Paris, Cedex 13, France

Authors for correspondence (e-mails: matthias.peter{at}bc.biol.ethz.ch; tyers{at}mshri.on.ca; pintard.lionel{at}ijm.jussieu.fr)

Accepted 26 November 2008

The COP9 signalosome (CSN) is an evolutionarily conserved macromolecular complex that interacts with cullin-RING E3 ligases (CRLs) and regulates their activity by hydrolyzing cullin-Nedd8 conjugates. The CSN sequesters inactive CRL4^Ddb2, which rapidly dissociates from the CSN upon DNA damage. Here we systematically define the protein interaction network of the mammalian CSN through mass spectrometric interrogation of the CSN subunits Csn1, Csn3, Csn4, Csn5, Csn6 and Csn7a. Notably, we identified a subset of CRL complexes that stably interact with the CSN and thus might similarly be activated by dissociation from the CSN in response to specific cues. In addition, we detected several new proteins in the CRL-CSN interactome, including Dda1, which we characterized as a chromatin-associated core subunit of multiple CRL4 proteins. Cells depleted of Dda1 spontaneously accumulated double-stranded DNA breaks in a similar way to Cul4A-, Cul4B- or Wdr23-depleted cells, indicating that Dda1 interacts physically and functionally with CRL4 complexes. This analysis identifies new components of the CRL family of E3 ligases and elaborates new connections between the CRL and CSN complexes.

Key words: Ubiquitin-dependent proteolysis, Cullin-RING E3 ligases, Neddylation, Deneddylation, Dda1

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