Schematic representation of the functional regions of EWS (656 AA), EWS/ATF1 (537 AA), and EWS/FLI1 (476 AA). The translocation t(11; 22)(q24; q12) encodes the fusion protein EWS/FLI, composed of the NTD of EWS (chromosome 22) fused in-frame to the CTD of FLI (chromosome 11). The translocation t(12; 22)(q13; q12) encodes the fusion protein EWS/ATF1, a fusion in-frame of the NTD of EWS (chromosome 22) to the CTD of ATF1 (chromosome 12). EWS contains an N-terminal transcriptional activation domain (EAD, SYQG rich region; G/P/T rich, 31 tandem repeats) and a C-terminal RNA-binding domain (RBD). The N-terminus of EAD (residues 1–82) binds to RNA Pol II (subunit Rpb7) and to ZFM1/SF1. The RBD contains an RNA-recognition motif (RRM, consisting of about 100 conserved residues), RGG boxes (RGG1, RGG2, and RGG3 of 5, 3, and 12 motifs), and a putative zinc finger (ZN). The EWS/ATF1 is composed of the EAD (residues 1–325, comprising also the IQ domain) fused to the C-terminal region of ATF1 (residues 66–271). The bZIP domain of ATF1 mediates dimerization and DNA binding, Q2 is a glutamine-rich constitutive activation domain, and β is required for activity (contains a critical motif DLSSD). EWS-FLI1 is composed of the EAD (residues 1–264) fused to the CTD of Fli1 (residues 241–452), containing its DNA-BD (DNA-binding domain) and Pro (proline-rich activation domain).