The Pax3-FKHR oncoprotein is unresponsive to the Pax3-associated repressorhDaxx

The Pax3-FKHR fusion protein is present in alveolar rhabdomyosarcoma and re sults from the t(2;13) (q35; q14) chromosomal translocation. Its oncogenic activity is dependent on a combination of protein-DNA and protein-protein i nteractions mediated by the Pax3 homeodomain recognition helix. In this rep ort we demonstrate that human Daxx (hDaxx) interacts with Pax3 in vivo and with DNA-bound Pax3 in vitro. This interaction is mediated primarily throug h the homeodomain recognition helix with the additional involvement of the octapeptide domain and its N-terminal flanking amino acids. Through this in teraction hDaxx represses the transcriptional activity of Pax3 by similar t o 80%. The Pax3-FKHR fusion is unresponsive to this repressive effect despi te an observed endogenous interaction with hDaxx in a rhabdomyosarcoma tumo r cell line. Therefore, these data support the model that fusion of FKHR to Pax3 not only adds a strong transactivation domain, but also deregulates t ranscriptional control of Pax3 by overriding the natural repressive effect of hDaxx.