Prion-like Domains Program Ewing's Sarcoma

Abstract

Prion-like domains have emerged as important drivers of neurodegenerative disease. Now, Boulay et al. establish that the translocated prion-like domain of the oncogenic EWS-FLI1 fusion protein enables phase-separation events, which inappropriately recruit chromatin-remodeling factors to elicit the aberrant transcriptional programs underlying Ewing's sarcoma.

Figure 1. Domain Architecture of EWSR1, FLI1, and EWS-FLI1

EWSR1 contains an N-terminal prion-like domain (PrLD), a glycine-rich domain (Gly-rich), a RNA-recognition motif (RRM), two RGG domains separated by a zinc-finger domain (ZNF), and a C-terminal PY-nuclear localization sequence (PY-NLS). FLI1 harbors an N-terminal activation domain (AD) and a C-terminal DNA-binding domain (DBD). In the EWS-FLI1 (type 1) fusion protein, amino acids 1–264 of the EWSR1 PrLD are fused with residues 219–452 of FLI1. Note that the SYGQ1 and SYGQ2 portions of the EWSR1 PrLD could substitute for the larger EWSR1 PrLD fragment (residues 1–264) and induce the gene-expression programs of Ewing’s sarcoma when fused to FLI1 (Boulay et al., 2017).