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J. Biol. Chem., Vol. 281, Issue 38, 27784-27793, September 22, 2006

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Interplay between Ku, Artemis, and the DNA-dependent Protein Kinase Catalytic Subunit at DNA Ends^*

Jérôme Drouet, Philippe Frit, Christine Delteil, Jean-Pierre de Villartay^¶, Bernard Salles¹, and Patrick Calsou

From the Institut de Pharmacologie et de Biologie Structurale, CNRS UMR 5089, 205 Route de Narbonne, 31077 Toulouse, Cedex 4, France, INSERM, Hôpital Necker-Enfants Malades, U768, UnitéDéveloppement Normal et Pathologique du Système Immunitaire, F-75015 Paris, France, and ^¶Université Paris Descartes, Faculté de Médecine René Descartes, F-75005 Paris, France

Repair of DNA double strand breaks (DSB) by the nonhomologous end-joining pathway in mammals requires at least seven proteins involved in a simplified two-step process: (i) recognition and synapsis of the DNA ends dependent on the DNA-dependent protein kinase (DNA-PK) formed by the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs in association with Artemis; (ii) ligation dependent on the DNA ligase IV·XRCC4·Cernunnos-XLF complex. The Artemis protein exhibits exonuclease and endonuclease activities that are believed to be involved in the processing of a subclass of DSB. Here, we have analyzed the interactions of Artemis and nonhomologous end-joining pathway proteins both in a context of human nuclear cell extracts and in cells. DSB-inducing agents specifically elicit the mobilization of Artemis to damaged chromatin together with DNA-PK and XRCC4/ligase IV proteins. DNA-PKcs is necessary for the loading of Artemis on damaged DNA and is the main kinase that phosphorylates Artemis in cells damaged with highly efficient DSB producers. Under kinase-preventive conditions, both in vitro and in cells, Ku-mediated assembly of DNA-PK on DNA ends is responsible for a dissociation of the DNA-PKcs·Artemis complex. Conversely, DNA-PKcs kinase activity prevents Artemis dissociation from the DNA-PK·DNA complex. Altogether, our data allow us to propose a model in which a DNA-PKcs-mediated phosphorylation is necessary both to activate Artemis endonuclease activity and to maintain its association with the DNA end site. This tight functional coupling between the activation of both DNA-PKcs and Artemis may avoid improper processing of DNA.

Received for publication, March 30, 2006 , and in revised form, July 14, 2006.

^* This work was supported in part by grants from the Association pour la Recherche sur le Cancer, the Ligue Nationale Contre le Cancer, Electricité de France, and the Commisariat à l'Energie Atomique. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Institut de Pharmacologie et de Biologie Structurale, CNRS, UMR 5089, 205 Route de Narbonne, 31077 Toulouse Cedex 4, France. Tel.: 33-5-61-17-59-36; Fax: 33-5-61-17-59-33; E-mail: bernard.salles{at}ipbs.fr.

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