Essential Effectors of Myc function

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DESCRIPTION (provided by applicant): We are interested in determining the function of the c-myc proto-oncogene in normal cells and how misregulation or overexpression of the c-Myc protein can induce cell transformation. Functional studies have demonstrated that a segment from the N-terminus of Myc (called Myc homology box II or MBII) is essential for oncogenic transformation. In the last granting period, we were able to purify and characterize a nuclear cofactor, called TRRAP, for TRansformation/tRansactivation Associated Protein, that binds to Myc through MBII. The discovery of TRRAP has proven to be a seminal discovery in the Myc field because it provided a link between Myc and chromatin modifying complexes that acetylate histones. Localized histone acetylation has been shown both biochemically and genetically to facilitate gene activation. This project will address the functional consequences of TRRAP complex recruitment by c-Myc. We will also explore the more global function of TRRAP itself and the growing number of TRRAP containing nuclear complexes. The specific aims are as follows: 1) We will characterize the structure and function of DNA Methyltransferase Associated Protein (DMAP1), a newly discovered protein associated with both Myc and TRRAP. We will test the hypothesis that DMAP1 is a critical Myc-associated histone acetyltransferase. 2) We will explore the function of the nuclear actin-related protein BAF53 and its role in chromatin modifying complexes. Specifically, we will determine the biochemical basis for the dominant inhibitory activity of a BAF53 mutant protein with a small deletion in a critical functional domain. 3) We will explore the function of the Enhancer of polycomb protein, which marks a unique set of HAT complexes. We will try to determine how complexes between TRRAP and Epc1 differ from those containing TRRAP and DMAP1, and we will examine the role of these complexes in gene regulation. 4) We will determine the role of individual HATs and cofactors in the activation of specific cellular target genes. The role of each protein in the activation of the silent TERT gene will be addressed. We will test for synergism between Myc and the Sp1 transcription factor in the activation of the silent telomerase reverse transcriptase (TERT) gene.