Ewing sarcoma protein: a key player in human cancer

Abstract

The Ewing sarcoma protein (EWS) is a well-known player in cancer biology for the specific translocations occurring in sarcomas. The EWS-FLI1 gene fusion is the prototypical translocation that encodes the aberrant, chimeric transcription factor, which is a landmark of Ewing tumors. In all described Ewing sarcoma oncogenes, the EWS RNA binding domains are completely missing; thus RNA binding properties are not retained in the hybrid proteins. However, it is currently unknown whether the absence of EWS function in RNA metabolism plays a role in oncogenic transformation or if EWS plays a role by itself in cancer development besides its contribution to the translocation. In this regard, recent reports have highlighted an essential role for EWS in the regulation of DNA damage response (DDR), a process that counteracts genome stability and is often deregulated in cancer cells. The first part of this review will describe the structural features of EWS and its multiple roles in the regulation of gene expression, which are exerted by coordinating different steps in the synthesis and processing of pre-mRNAs. The second part will examine the role of EWS in the regulation of DDR- and cancer-related genes, with potential implications in cancer therapies. Finally, recent advances on the involvement of EWS in neuromuscular disorders will be discussed. Collectively, the information reviewed herein highlights the broad role of EWS in bridging different cellular processes and underlines the contribution of EWS to genome stability and proper cell-cycle progression in higher eukaryotic cells.

Figure 1

Domain structure of TET proteins: the N-terminal activation domain and the C-terminal nucleic acid binding domain of TET proteins are schematized: the SYGQ rich domain, RGG boxes, and the RNA binding domain (RBD), Cys2-Cys2 zinc finger (ZF). Below the scheme, the exons encoding each domain are indicated for EWS, FUS/TLS, and TAF15, respectively [17, 18]. In the upper part of the figure the proteins that have been described to interact with either the DNA activation domain or the nucleic acid binding domain of EWS are listed.

Figure 2

Schematic representation of the cross-talk between the transcriptional and splicing machineries mediated by RNAPII, EWS, and YB-1. (a) In normal condition EWS associates with the preinitiation complex TFIID, with the RNAPII and with its target transcripts and associated genomic regions; once the transcription has started, EWS jumps on the nascent RNA promoting specific AS events. (b) Upon CPT treatment EWS dissociates from YB-1 and from the spliceosome [64]. Similarly, upon low intensity UV light irradiation EWS dissociates from active transcription sites and relocalizes to nucleoli [51]. As a result, EWS regulated AS events cannot occur [51, 64].