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Abstract
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.
Supplemental material for this article may be found at http://mcb.asm.org/.
We thank C. Jacquemont and A. Simoni for help at certain stages of this study; M. Argentini for helpful discussions and advice; G. Duval and M. Oulad-Abdelghani for antibody preparation, B. Amati, M. Cole, J. Chen, K. Helin, D. M. Livingston and D. Trouche for kindly providing antibodies; and T. Hilton and E. Gaillard for comments on the manuscript.
F.R. was supported by a fellowship from the CNRS and the Région Alsace, S.H. was supported by a fellowship from MRT, Z.N. was supported by a fellowship from the EU (grant HPRN-CT-2004-504228), and U.D. was supported by an FRSQ scholarship. J.-Y.M. is a CIHR new investigator. This work was supported by EU grants (HPRN-CT-2000-00087, HPRN-CT-2000-00088, HPRN-CT-2004-504228, and LSHG-CT-2004-502950), AICR, INSERM, the CNRS, the Hôpital Universitaire de Strasbourg, the ARC, the Fondation pour la Recherche Medicale, and the Ministere de la Recherche (ACI) (to L.T.) and by an NCIC grant (16331) (to J.-Y.M.).