Structure-function based molecular relationships in Ewing's sarcoma.

Roumiana Todorova

doi:10.1155/2015/798426

Abstract

Ewing's Sarcoma Oncogene (ews) on chromosome 22q12 is encoding a ubiquitously expressed RNA-binding protein (EWS) with unknown function that is target of tumor-specific chromosomal translocations in Ewing's sarcoma family of tumors. A model of transcription complex was proposed in which the heterodimer Rpb4/7 binds to EAD, connecting it to Core RNA Pol II. The DNA-binding domain, provided by EFP, is bound to the promoter. Rpb4/7 binds RNA, stabilizing the transcription complex. The complex Rpb4/7 can stabilize the preinitiation complexes by converting the conformation of RNA Pol II. EWS may change its conformation, so that NTD becomes accessible. Two different mechanisms of interaction between EWS and RNA Pol II are proposed: (I) an intermolecular EWS-EWS interaction between two molecules, pushing conformation from “closed” to “open” state, or (II) an intramolecular interaction inside the molecule of EWS, pushing conformation of the molecule from “closed” to “open” state. The modified forms of EWS may interact with Pol II subunits hsRpb5 and hsRpb7. The EWS and EFPs binding partners are described schematically in a model, an attempt to link the transcription with the splicing. The proposed model helps to understand the functional molecular interactions in cancer, to find new partners and ways to treat cancer.

Highlights

The chromosomal translocations that result in the fusion of the amino transactivation domain of TET proteins with the DNA-binding domain of ETS-related transcription factor proteins are the common determinants of cancer [1]
The modified forms of Ewing’s sarcoma (EWS) may interact with Pol RNA polymerase II NTD (II) subunits hsRpb5 and hsRpb7
Proteins associated with human diseases, such as cancer, are enriched in intrinsic disorder: they enter in high-specificitylow-affinity interactions and one-to-many binding mode by which a single Intrinsically disordered proteins (IDPs)/IDR binds to multiple structurally diverse partners, accomplished by their plasticity [21]

Summary

Introduction

The chromosomal translocations that result in the fusion of the amino transactivation domain of TET proteins with the DNA-binding domain of ETS-related transcription factor proteins are the common determinants of cancer [1]. Ewing’s sarcoma family of tumors (ESFTs) is an example of how genome research has advanced the understanding of the molecular pathogenesis of the disease. Modulation of EWS/FLI1 expression is a therapeutic goal that may influence the course of the disease [2]. The clarification of the mechanism of EWS function may help to understand the functional molecular interactions in cancer, to find new partners and ways to treat cancer. Ewing’s Sarcoma Oncogene on chromosome 22q12 is encoding a ubiquitously expressed RNA-binding protein, the Ewing’s sarcoma (EWS) protein, a member of the TET (TLS/EWS/TAF15) family of RNA- and DNA-binding proteins

Methods

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Conclusion