Paronetto, Maria PaolaBernardis, IsabellaVolpe, ElisabettaBechara, EliasSebestyén, EndreEyras Jiménez, EduardoValcárcel, J. (Juan)2015-06-042015-06-042014Paronetto MP, Bernardis I, Volpe E, Bechara E, Sebestyen E, Eyras E, Valcarcel J. Regulation of FAS exon definition and apoptosis by the ewing sarcoma protein. Cell Reports. 2014; 7: 1211-1226. DOI 10.1016/j.celrep.2014.03.0772211-1247http://hdl.handle.net/10230/23722The Ewing sarcoma protein EWS is an RNA and DNA binding protein implicated in transcription, pre-mRNA splicing, and DNA damage response. Using CLIP-seq, we identified EWS RNA binding sites in exonic regions near 5′ splice sites. A prominent target was exon 6 of the FAS/CD95 receptor, which is alternatively spliced to generate isoforms with opposing activities in programmed cell death. Depletion and overexpression experiments showed that EWS promotes exon 6 inclusion and consequently the synthesis of the proapoptotic FAS/CD95 isoform, whereas an EWS-FLI1 fusion protein characteristic of Ewing sarcomas shows decreased activity. Biochemical analyses revealed that EWS binding promotes the recruitment of U1snRNP and U2AF65 to the splice sites flanking exon 6 and therefore exon definition. Consistent with a role for EWS in the regulation of programmed cell death, cells depleted of EWS show decreased sensitivity to FAS-induced apoptosis, and elevated EWS expression enhances apoptosis in EWS-haploinsufficient Ewing sarcoma cells.application/pdfeng© 2014, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 International http://creativecommons.org/licenses/by-nc-nd/3.0/ http://dx.doi.org/10.1016/j.celrep.2014.03.077ProteïnesAntígens CDRNAinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.celrep.2014.03.077info:eu-repo/semantics/openAccess