Disease relevance of TRRAP

• Antisense TRRAP RNA inhibited estrogen-dependent cell growth of breast cancer cells [1].
• The adenovirus E1A oncoprotein recruits the cellular TRRAP/GCN5 histone acetyltransferase complex [2].
• The conjugative transfer region 1 (Tra1) of the IncHI1 plasmid R27 was subjected to DNA sequence analysis, mutagenesis, genetic complementation, and an H-pilus-specific phage assay [3].

High impact information on TRRAP

• TRRAP also interacts specifically with the E2F-1 transactivation domain [4].
• Expression of transdominant mutants of the TRRAP protein or antisense RNA blocks c-Myc- and E1A-mediated oncogenic transformation [4].
• Chromatin-immunoprecipitation experiments demonstrate that the Gal4-Tra1 interaction is required for recruitment of SAGA to the upstream activating sequence (UAS), and SAGA, in turn, recruits the Mediator complex to the UAS [5].
• Down-regulation of cyclin D2 mRNA expression in differentiating HL60 cells is preceded by a switch of promoter occupancy from Myc/Max to Mad/Max complexes, loss of TRRAP binding, increased HDAC1 binding, and histone deacetylation [6].
• Binding of Myc induces cyclin D2 expression and histone acetylation at a single nucleosome in a MycBoxII/TRRAP-dependent manner [6].

Biological context of TRRAP

• E1A associates with transcriptional regulatory complexes containing p400 and TRRAP involved in chromatin remodeling and decondensation [2].
• We discuss the possibility that PAF400 may play a role in signaling of DNA damage to p53 by stimulation of p53 acetylation [7].
• TRRAP is a component of several multiprotein acetyltransferase complexes implicated in both transcriptional regulation and DNA repair [8].
• Transcriptional regulation of the mdm2 oncogene by p53 requires TRRAP acetyltransferase complexes [8].
• Furthermore, transfection of cells with antisense TRRAP blocks p53-dependent transcription of mdm2 [8].

Anatomical context of TRRAP

• However, recruitment of TRRAP by c- or N-Myc is dispensable for the partial induction of several basally expressed genes in exponentially growing primary and immortalized fibroblasts [9].
• We previously isolated the TRRAP/TIP60 complex from HeLa cells (Cai, Y., Jin, J., Tomomori-Sato, C., Sato, S., Sorokina, I., Parmely, T. J., Conaway, R. C., and Conaway, J. W. (2003) J. Biol. Chem. 278, 42733-42736) [10].
• 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 [11].
• To address this issue, we used hepatic cell lines (HepG2) with reduced endogenous TRRAP expression through antisense RNA expression or with overexpressed TRRAP or other major coactivators [12].

Associations of TRRAP with chemical compounds

• The alanine-replaced BAF53 mutants also stimulated p53-dependent transcription, in which the SWI/SNF and TRRAP complexes are involved [13].
• Estrogen stimulation enhanced the c-MYC-ERalpha interaction and facilitated the association of ERalpha, c-MYC, and the coactivator TRRAP with these estrogen-responsive promoters, resulting in chromatin remodeling and increased transcription [14].

Physical interactions of TRRAP

• In vitro analysis demonstrates that p53 directly binds to a TRRAP domain previously shown to be an activator docking site [8].
• These findings suggest a model in which p53 directly recruits a TRRAP/acetyltransferase complex to the mdm2 gene to activate transcription [8].

Regulatory relationships of TRRAP

• An hGCN5/TRRAP histone acetyltransferase complex co-activates BRCA1 transactivation function through histone modification [15].
• Expression of antisense TRRAP RNA in HepG2 cells abolished the ligand-induced expression of LXRalpha target genes [12].

Other interactions of TRRAP

• Accordingly, wild-type L-Myc is much less efficient in TRRAP binding, activation of the silent TERT gene, and transformation of primary fibroblasts [9].
• E2F transcriptional activation requires TRRAP and GCN5 cofactors [16].
• Here we report cloning and characterization of the 400 kDa PCAF-associated factor referred to as PAF400 [7].
• Furthermore, recruitment of TRRAP is required for c-Myc- or N-Myc-mediated oncogenic transformation but not for the partial restoration of the growth defect in myc-null fibroblasts [9].
• However, unlike the other members of the ATM superfamily, PAF400 is not a protein kinase as judged from the lack of kinase motif and autophosphorylation activity [7].

Analytical, diagnostic and therapeutic context of TRRAP

• Finally, using chromatin immunoprecipitation, we demonstrate direct p53-dependent recruitment of TRRAP to the mdm2 promoter, followed by increased histone acetylation [8].
• By using double immunopurification, mass spectrometry, and gel filtration, we describe the stable association of TRRAP with the MRN complex [11].

References