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Aberrant gene activation in synovial sarcoma relies on SSX specificity and increased PRC1.1 stability

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 te...

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Main Authors: Benabdallah, Nezha S. (Author) , Dalal, Vineet (Author) , Scott, R. Wilder (Author) , Marcous, Fady (Author) , Sotiriou, Afroditi (Author) , Kommoss, Felix (Author) , Pejkovska, Anastasija (Author) , Gaspar, Ludmila (Author) , Wagner, Lena (Author) , Sánchez-Rivera, Francisco J. (Author) , Ta, Monica (Author) , Thornton, Shelby (Author) , Nielsen, Torsten O. (Author) , Underhill, T. Michael (Author) , Banito, Ana (Author)
Format: Article (Journal)
Language:English
Published: 21 September 2023
In: Nature structural & molecular biology
Year: 2023, Pages: 1-33
ISSN:1545-9985
DOI:10.1038/s41594-023-01096-3
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41594-023-01096-3
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41594-023-01096-3
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Author Notes:Nezha S. Benabdallah, Vineet Dalal, R. Wilder Scott, Fady Marcous, Afroditi Sotiriou, Felix K. F. Kommoss, Anastasija Pejkovska, Ludmila Gaspar, Lena Wagner, Francisco J. Sánchez-Rivera, Monica Ta, Shelby Thornton, Torsten O. Nielsen, T. Michael Underhill, Ana Banito
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Summary: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.
Item Description:Gesehen am 07.11.2023
Physical Description:Online Resource
ISSN:1545-9985
DOI:10.1038/s41594-023-01096-3

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