Functional Interactions in Transcription and Splicing of Ewing’s Sarcoma

Ewing’s sarcoma (EWS) protein is a member of the TET (TLS/EWS/TAF15) family of RNA and DNA-binding proteins with unknown cellular role. EWS protein is encoded by the EWS oncogene on chromosome 22q12, a target of chromosomal translocations in Ewing’s sarcoma tumors. The exact mechanism of EWS participation in gene expression and pathogenesis of the resulting cancers is not defined. The binding partners of native EWS and EWS fusion proteins (EFPs) are described schematically in a model, an attempt to link the transcription with the splicing. The experimental data about the partnerships of EWS and EFPs are summarized, which may lead to better understanding of their function. 1. Introduction Transcription and splicing seems to be connected by proteins with roles in both processes, coordinating them, such as TET proteins, since their NTDs mediate interactions with RNA polymerase II (Pol II), while their CTD binds to splicing factors. Thus TET proteins may recruit splicing factors to the Pol II, which coordinates pre-mRNA processing events [1]. The participation of native Ewing’s sarcoma protein (EWS) and its oncogenic fusion proteins (EFPs), as well as their reported binding partners in transcription and splicing, could be described schematically by a model to link the transcription with the splicing in ESFTs. Some EWS and EWS/FLI1 interacting partners (including Pol II subunits) are implicated in transcriptome and spliceosome and are directly involved in mRNA synthesis or splicing. 1.1. Ewing’s Sarcoma Ewing’s sarcoma, first described by James Ewing in 1921, is still a cryptic malignancy. Ewing’s sarcoma family tumors (ESFTs) afflict children and young adults, encompassing Ewing’s Sarcoma of bone, extraosseous (soft-tissue) Ewing’s sarcoma, primitive neuroectodermal Tumor (PNET), and Askin’s tumor. ESFTs have high propensity to metastasize in bone, bone marrow, and lung. ESFTs are aggressive round cell tumors of putative stem cell origin, for which prognostic biomarkers and novel treatments are needed [2, 3]. ESFTs are chemotherapy-sensitive cancers, and even patients with metastatic disease commonly achieve remission. Diagnosis of Ewing tumor is based on pathologic and molecular findings [4]. The EFPs are promoter-specific transcriptional activators, due to EWS-activation domain (EAD) and a DNA-binding domain (DBD) from the fusion partner. About 85% of Ewing tumours carry the most frequent EWSR1/FLI1 fusion gene that is critically important for maintaining the tumor phenotype of the disease. The EWS/FLI1 may be fully transforming only in a mutated cell