Role of the Paf complex for the control of transcription by Drosophila Myc

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Myc proto-oncoproteins are essential regulators of normal development and they play a major role in human cancer. They function as transcription factors that activate or repress a large number of different genes. However, the mechanism by which Myc controls the expression of its targets is not fully understood. To identify physiologically relevant transcriptional co-factors for Myc, and thereby decipher Myc’s mechanism of transactivation, we have conducted a pilot RNAi screen in Drosophila S2 cells. This screen resulted in the identification of several components of the Paf (“Polymerase II Associated Factor”) complex, and of other proteins known to interact with Paf. In preliminary experiments we demonstrated that the Paf complex is important for controlling Myc’s targets in S2 cells and Myc’s biological activities in vivo, and that the subunit Atu / Leo1 physically interacts with Myc. This application now proposes to characterize the interaction between Myc and the Paf complex (plus associated proteins), and to describe the molecular basis for their effect on transcription. In addition, we want to extend the screen for Myc cofactors to the full Drosophila genome, to obtain a complete list of the factors that normally control the activity of Myc.