Differential interaction of PRMT1 with RGG-boxes of the FET family proteins EWS and TAF15.

The FET sub-family (FUS/TLS, EWS, TAF15) of RNA-binding proteins have remarkably similar overall structure but diverse biological and pathological roles. The molecular basis for FET protein specialization is largely unknown. Gly-Arg-Rich regions (RGG-boxes) within FET proteins are targets for methylation by Protein-Arginine-Methyl-Transferase-1 (PRMT1) and substrate capture is thought to involve electrostatic attraction between positively charged polyRGG substrates and negatively charged surface channels of PRMT1.

RGG boxes within the TET/FET family of RNA-binding proteins are functionally distinct.

The multi-functional TET (TAF15/EWS/TLS) or FET (FUS/EWS/TLS) protein family of higher organisms harbor a transcriptional-activation domain (EAD) and an RNA-binding domain (RBD). The transcriptional activation function is, however, only revealed in oncogenic TET-fusion proteins because in native TET proteins it is auto-repressed by RGG-boxes within the TET RBD. Auto-repression is suggested to involve direct cation-pi interactions between multiple Arg residues within RGG boxes and EAD aromatics.

The RNA Pol II sub-complex hsRpb4/7 is required for viability of multiple human cell lines.

The evolutionarily conserved RNA Polymerase II Rpb4/7 sub-complex has been thoroughly studied in yeast and impacts gene expression at multiple levels including transcription, mRNA processing and decay. In addition Rpb4/7 exerts differential effects on gene expression in yeast and Rpb4 is not obligatory for yeast (S. cerevisiae) survival.

In vitro activity of the EWS oncogene transcriptional activation domain.

Aberrant chromosomal fusion of the Ewings sarcoma oncogene (EWS) to several different cellular partners gives rise to the Ewing's family of oncogenic proteins [EWS fusion proteins (EFPs)] and associated tumors (EFTs). EFPs are potent transcriptional activators dependent on the N-terminal region of EWS [the EWS activation domain (EAD)], and this function is thought to be central to EFT oncogenesis and maintenance. Thus, EFPs are promising therapeutic targets, and detailed molecular studies of the EAD will be pivotal for exploring this potential.