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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,5,20]]},"abstract":"<jats:p>\n                    Ewing sarcoma (EwS) is an aggressive cancer of bone and soft tissue that predominantly affects children and young adults. A chromosomal translocation joins the low-complexity domain (LCD) of the RNA-binding protein EWS (EWS\n                    <jats:sup>LCD<\/jats:sup>\n                    ) with the DNA-binding domain of Friend leukemia integration 1 (FLI1\n                    <jats:sup>DBD<\/jats:sup>\n                    ), creating EWS::FLI1, a potent fusion oncoprotein essential for EwS development and responsible for over 85% of EwS tumors. EWS::FLI1 forms biomolecular condensates in vivo and promotes tumorigenesis through mediation of aberrant transcriptional changes and by interfering with the normal functions of nucleic acid-binding proteins like EWS through a dominant-negative mechanism. In particular, the expression of EWS::FLI1 in EwS directly interferes with the biological functions of EWS leading to alternate splicing events and defects in DNA-damage repair pathways. Though the EWS\n                    <jats:sup>LCD<\/jats:sup>\n                    is capable of phase separation, here we report a direct interaction between FLI1\n                    <jats:sup>DBD<\/jats:sup>\n                    and EWS\n                    <jats:sup>LCD<\/jats:sup>\n                    that enhances condensate formation and alters the physical properties of the condensate. This effect was conserved for three related E-twenty-six transformation-specific (ETS) DNA-binding domains (DBDs) while DNA binding blocked the interaction with EWS\n                    <jats:sup>LCD<\/jats:sup>\n                    and inhibited EWS::FLI1 condensate formation. NMR spectroscopy and mutagenesis studies confirmed that ETS DBDs transiently interact with EWS\n                    <jats:sup>LCD<\/jats:sup>\n                    via the ETS DBDs \u201cwings.\u201d Together these results revealed that ETS DBDs, particularly FLI1\n                    <jats:sup>DBD<\/jats:sup>\n                    , enhance EWS\n                    <jats:sup>LCD<\/jats:sup>\n                    condensate formation and rigidity, supporting a model in which electrostatic and structural interactions drive condensate dynamics with implications for EWS::FLI1-mediated transcriptional regulation in EwS.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2221823122","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T11:59:56Z","timestamp":1747396796000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":24,"title":["Phase separation of the oncogenic fusion protein EWS::FLI1 is modulated by its DNA-binding domain"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3012-6814","authenticated-orcid":false,"given":"Emily E.","family":"Selig","sequence":"first","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]},{"name":"Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5908-0912","authenticated-orcid":false,"given":"Erich J.","family":"Sohn","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]},{"name":"Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiola","family":"Stoja","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]},{"name":"Department of Cell Systems and Anatomy, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alma K.","family":"Moreno-Romero","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]},{"name":"Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivani","family":"Akula","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]},{"name":"Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Xu","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]},{"name":"Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J. R.","family":"Bishop","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]},{"name":"Department of Cell Systems and Anatomy, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6492-2803","authenticated-orcid":false,"given":"David S.","family":"Libich","sequence":"additional","affiliation":[{"name":"Greehey Children\u2019s Cancer Research Institute, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]},{"name":"Department of Biochemistry and Structural Biology, The University of Texas Health Science Center at San Antonio","place":["San Antonio"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0003-x"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.79.081507.103945"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/his.12269"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.036"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.10.033"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21690-7"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1201964"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","unstructured":"E. 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