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The Ewings Sarcoma Oncoprotein (EWS) interacts with several components of the mammalian transcriptional and pre-mRNA splicing machinery and is also found in the cytoplasm and even on the cell surface. The apparently diverse cellular functions of EWS are, however, not well characterized. EWS harbours a potent N-terminal transcriptional activation domain (the EAD) that is revealed in the context of oncogenic EWS-fusion proteins (EFPs) and a C-terminal RNA-binding domain (RBD) that recruits pre-mRNA splicing factors and may couple transcription and splicing. In contrast to EFPs, the presumed transcriptional role of normal EWS remains enigmatic. Here, we report that multiple RGG-boxes within the RBD are necessary and sufficient for cis-repression of the EAD and that RGG-boxes can also repress in-trans, within dimeric partners. Lys can functionally substitute for Arg, indicating that the basic nature of the Arg side chain is the critical determinant of RGG-box-mediated repression. In addition to the EAD, RGG-boxes can repress a broad range of activation domains (including those of VP16, E1a and CREB), but repression can be alleviated by the simultaneous presence of more than one activation domain. We therefore propose that a key function of RGG boxes within native EWS is to restrict promiscuous activation by the EAD while still allowing EWS to enter functional transcription complexes and participate in other transactions involving pre-mRNAs.

RGG-boxes of the EWS oncoprotein repress a range of transcriptional activation domains