STAGA Recruits Mediator to the MYC Oncoprotein To Stimulate Transcription and Cell Proliferation

Abstract

Activation of eukaryotic gene transcription involves the recruitment by DNA-binding activators of multiprotein histone acetyltransferase (HAT) and Mediator complexes. How these coactivator complexes functionally cooperate and the roles of the different subunits/modules remain unclear. Here we report physical interactions between the human HAT complex STAGA (SPT3-TAF9-GCN5-acetylase) and a “core” form of the Mediator complex during transcription activation by the MYC oncoprotein. Knockdown of the STAF65γ component of STAGA in human cells prevents the stable association of TRRAP and GCN5 with the SPT3 and TAF9 subunits; impairs transcription of MYC-dependent genes, including MYC transactivation of the telomerase reverse transcriptase (TERT) promoter; and inhibits proliferation of MYC-dependent cells. STAF65γ is required for SPT3/STAGA interaction with core Mediator and for MYC recruitment of SPT3, TAF9, and core Mediator components to the TERT promoter but is dispensable for MYC recruitment of TRRAP, GCN5, and p300 and for acetylation of nucleosomes and loading of TFIID and RNA polymerase II on the promoter. These results suggest a novel STAF65γ-dependent function of STAGA-type complexes in cell proliferation and transcription activation by MYC postloading of TFIID and RNA polymerase II that involves direct recruitment of core Mediator.

ACKNOWLEDGMENTS

We thank J. C. Barrett, R. Bernards, M. D. Cole, R. A. Currie, S. Malik, Y. Nakatani, R. G. Roeder, and L. Tora for generous gifts of reagents. We also thank R. G. Roeder and A. Gamper for communication of unpublished results and R. G. Roeder and S. Malik for stimulating discussions and comments on the manuscript. We also thank L. Tora for critical comments on the manuscript.

This work was supported by grant CA100464 from the National Institutes of Health.