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Molecular and Cellular Biology, January 2006, p. 402-412, Vol. 26, No. 2
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.2.402-412.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Transcriptional Histone Acetyltransferase Cofactor TRRAP Associates with the MRN Repair Complex and Plays a Role in DNA Double-Strand Break Repair{dagger}

Flavie Robert,1,{ddagger} Sara Hardy,1,{ddagger} Zita Nagy,1 Céline Baldeyron,2 Rabih Murr,3 Ugo Déry,4 Jean-Yves Masson,4 Dora Papadopoulo,2 Zdenko Herceg,3 and Làszlò Tora1*

Department of Transcription, Institut de Génétique et de Biologie Moleculaire et Cellulaire, UMR 7104 CNRS, F-67404 Illkirch Cedex, CU de Strasbourg, France,1 UMR 218 of CNRS, Institut Curie, F-75248 Paris Cedex 05, France,2 International Agency for Research on Cancer, World Health Organization, 150 Cours Albert Thomas, F-69372 Lyon, France,3 Centre de Recherche, L'Hôtel-Dieu-de-Québec, Université Laval, Quebec, Canada4

Received 6 April 2005/ Returned for modification 1 May 2005/ Accepted 21 October 2005

Transactivation-transformation domain-associated protein (TRRAP) is a component of several multiprotein histone acetyltransferase (HAT) complexes implicated in transcriptional regulation. TRRAP was shown to be required for the mitotic checkpoint and normal cell cycle progression. MRE11, RAD50, and NBS1 (product of the Nijmegan breakage syndrome gene) form the MRN complex that is involved in the detection, signaling, and repair of DNA double-strand breaks (DSBs). By using double immunopurification, mass spectrometry, and gel filtration, we describe the stable association of TRRAP with the MRN complex. The TRRAP-MRN complex is not associated with any detectable HAT activity, while the isolated other TRRAP complexes, containing either GCN5 or TIP60, are. TRRAP-depleted extracts show a reduced nonhomologous DNA end-joining activity in vitro. Importantly, small interfering RNA knockdown of TRRAP in HeLa cells or TRRAP knockout in mouse embryonic stem cells inhibit the DSB end-joining efficiency and the precise nonhomologous end-joining process, further suggesting a functional involvement of TRRAP in the DSB repair processes. Thus, TRRAP may function as a molecular link between DSB signaling, repair, and chromatin remodeling.

* Corresponding author. Mailing address: Department of Transcription, Institut de Génétique et de Biologie Moleculaire et Cellulaire, UMR 7104 CNRS, F-67404 Illkirch Cedex, CU de Strasbourg, France. Phone: 33 3 88 65 34 44. Fax: 33 3 88 65 32 01. E-mail: laszlo{at}igbmc.u-strasbg.fr.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this study.

Molecular and Cellular Biology, January 2006, p. 402-412, Vol. 26, No. 2
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.2.402-412.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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