Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability Journal Article
| Authors: | Benabdallah, N. S.; Dalal, V.; Scott, R. W.; Marcous, F.; Sotiriou, A.; Kommoss, F. K. F.; Pejkovska, A.; Gaspar, L.; Wagner, L.; Sánchez-Rivera, F. J.; Ta, M.; Thornton, S.; Nielsen, T. O.; Underhill, T. M.; Banito, A. |
| Article Title: | Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability |
| Abstract: | The SS18-SSX fusion drives oncogenic transformation in synovial sarcoma by bridging SS18, a member of the mSWI/SNF (BAF) complex, to Polycomb repressive complex 1 (PRC1) target genes. Here we show that the ability of SS18-SSX to occupy H2AK119ub1-rich regions is an intrinsic property of its SSX C terminus, which can be exploited by fusion to transcriptional regulators beyond SS18. Accordingly, SS18-SSX recruitment occurs in a manner that is independent of the core components and catalytic activity of BAF. Alternative SSX fusions are also recruited to H2AK119ub1-rich chromatin and reproduce the expression signatures of SS18-SSX by engaging with transcriptional activators. Variant Polycomb repressive complex 1.1 (PRC1.1) acts as the main depositor of H2AK119ub1 and is therefore required for SS18-SSX occupancy. Importantly, the SSX C terminus not only depends on H2AK119ub1 for localization, but also further increases it by promoting PRC1.1 complex stability. Consequently, high H2AK119ub1 levels are a feature of murine and human synovial sarcomas. These results uncover a critical role for SSX-C in mediating gene deregulation in synovial sarcoma by providing specificity to chromatin and further enabling oncofusion binding by enhancing PRC1.1 stability and H2AK119ub1 deposition. © 2023, The Author(s). |
| Keywords: | genetics; cell cycle protein; mouse; animal; metabolism; animals; cell cycle proteins; mice; transcription initiation; chromatin; oncogene proteins, fusion; cell nucleus; synovial sarcoma; sarcoma, synovial; bmi1 protein; transcriptional activation; humans; human; oncogene fusion protein; polycomb repressive complex 1; prc1 protein, human |
| Journal Title: | Nature Structural and Molecular Biology |
| Volume: | 30 |
| Issue: | 11 |
| ISSN: | 1545-9993 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-11-01 |
| Start Page: | 1640 |
| End Page: | 1652 |
| Language: | English |
| DOI: | 10.1038/s41594-023-01096-3 |
| PUBMED: | 37735617 |
| PROVIDER: | scopus |
| PMCID: | PMC10643139 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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