The transcriptional histone acetyltransferase cofactor TRRAP associates with the MRN repair complex and plays a role in DNA double-strand break repair.
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.
Robert
Flavie
F
Department of Transcription, Institut de Génétique et de Biologie Moleculaire et Cellulaire, UMR 7104 CNRS, F-67404 Illkirch Cedex, CU de Strasbourg, France.
Hardy
Sara
S
Nagy
Zita
Z
Baldeyron
Céline
C
Murr
Rabih
R
Déry
Ugo
U
Masson
Jean-Yves
JY
Papadopoulo
Dora
D
Herceg
Zdenko
Z
Tora
Làszlò
L
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D002850:Chromatography, Gel; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D000076228:MRE11 Homologue Protein; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D018528:ATP-Binding Cassette Transporters; D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D000074443:Lysine Acetyltransferase 5; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C121766:MRE11 protein, human; C512689:Mre11a protein, mouse; C112156:NBN protein, human; C466108:Nijmegen breakage syndrome 1 protein, mouse; C113829:transformation-transcription domain-associated protein; C098489:KAT5 protein, human; C112158:RAD50 protein, human; C495198:Rad50 protein, mouse