The oncogenic fusion protein EWS-FLI1 promotes premature ageing of biomolecular condensates by catalyzing fibril formation

Abstract

AbstractEwing sarcoma (EwS) is an aggressive pediatric cancer of bone and soft tissue. A chromosomal translocation that joins the low-complexity domain of EWS (EWSLCD) with the DNA-binding domain of FLI1 (FLI1DBD) creates EWS-FLI1, a fusion oncoprotein essential for EwS development and accounts for 85% of all EwS cases. EWS-FLI1 acts as an aberrant transcription factor and interferes with the normal functions of nucleic acid-binding proteins via multivalent interactions and biomolecular condensation. The FLI1DBD was found to directly interact with the EWSLCD causing enhanced phase separation and induced hardening of EWSLCD condensates. Three related ETS DBDs (ERG, ETV1 and PU.1) also induced EWSLCD condensate hardening. DNA binding blocked the interaction with the EWSLCD, and NMR spectroscopy confirmed that ETS DBDs interact with EWSLCD via the DNA-binding interface. Our results provide a physical basis for the dominant-negative effect EWS-FLI1 exerts on EWS and highlight the need for further investigations of the FLI1DBD-EWSLCD interaction in vivo.