Abstract
Deregulation of the c-Myc oncoprotein (Myc) is implicated in many types of cancer. Myc is a sequence-specific transcription factor that regulates transcription of genes involved in the control of cell proliferation and apoptosis via mechanisms that are still poorly understood. Cell transformation by Myc involves its association with the transformation-transactivation domain-associated protein (TRRAP) and the human histone acetyltransferase (HAT) GCN5. TRRAP and GCN5 are components of a variety of shared and distinct multiprotein HAT complexes with diverse functions. Myc induces TRRAP recruitment and histone hyperacetylation at specific Myc-activated genes in vivo. However, the identity of the HAT complexes recruited by Myc and the roles of TRRAP and GCN5 in Myc function are still unclear. Here we show that Myc co-recruits TRRAP and GCN5 via direct physical interactions of its N-terminal activation/transformation domain with the human STAGA (SPT3-TAF-GCN5 acetylase) coactivator complex. We demonstrate that GCN5 and TRRAP cooperate to enhance transcription activation by the N-terminal activation domain of Myc in vivo and that this synergy requires both the SPT3/GCN5 interaction domain of TRRAP and the HAT activity of GCN5. Thus, TRRAP might function as an adaptor within the STAGA complex, which helps recruit GCN5 HAT activity to Myc during transcription activation.
Highlights
The c-Myc protein (Myc) is the most widely expressed member of a small family of highly related cellular oncoproteins that includes L-Myc and N-Myc
To address whether Myc associates with human STAGA and/or TFTC in vivo, we analyzed in co-immunoprecipitation experiments Myc interaction with components specific of these complexes (i.e. SPT3 and TAFs) that are not found in other known TRRAP or ADA/GCN5 complexes
In this report we identify the human STAGA coactivator complex as a TRRAP- and GCN5-containing histone acetyltransferase (HAT) complex that interacts with Myc in vivo and in vitro
Summary
TRRAP-HAT complexes in mediating transcription activation by Myc is suggested by the observed recruitment of TRRAP to certain Myc target genes during Myc-dependent activation in vivo and by a corresponding Myc-dependent increase in histone H3 and H4 hyperacetylation at target promoters/regulatory DNA regions, which depend on both MB2 and MB1-containing sequences [14, 15, 16]. We demonstrate an association of Myc:Max heterodimers with the human STAGA coactivator complex in vivo. We further provide the first evidence for synergistic functions of human GCN5 and TRRAP and a requirement for GCN5 HAT activity in mediating the transcription activating functions of the transformation/activation domain of Myc. our results strongly suggest a role for the human STAGA complex and associated GCN5 HAT activity in transcription activation by Myc
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