EWSR1

EWSR1, short for EWS RNA binding protein 1, is a gene located on chromosome 22q12 that encodes a widely expressed RNA-binding protein belonging to the FET family, which also includes FUS and TAF15. The gene plays roles in transcriptional regulation, RNA processing, chromatin remodeling, and the cellular response to DNA damage. EWSR1 is characterized by a strong N-terminal transcriptional activation domain and a C-terminal region containing an RNA recognition motif and zinc finger-like sequences that mediate RNA binding.

EWSR1 is notable for its involvement in chromosomal translocations that create fusion genes with various partners. The most well-known is EWSR1-FLI1, produced by t(11;22)(q24;q12), which drives oncogenesis in a large majority of Ewing sarcoma cases. Other fusion partners reported with EWSR1 include ERG, ETV1, ETV4, ATF1, CREB1, and DDIT3, among others, leading to a spectrum of mesenchymal tumors. For example, EWSR1-ATF1 is associated with clear cell sarcoma, and EWSR1-DDIT3 is characteristic of myxoid liposarcoma. These fusions generally encode chimeric transcription factors that aberrantly regulate gene expression, contributing to tumor development.

Diagnosis and clinical significance rely on detecting EWSR1 rearrangements, typically by fluorescence in situ hybridization (FISH) or reverse transcription–PCR assays on tumor tissue. The identification of an EWSR1 fusion helps distinguish Ewing-related sarcomas and other EWSR1-rearranged neoplasms from histologically similar tumors, guiding treatment decisions. Research continues into targeted therapies aimed at disrupting the function of these fusion proteins.