The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma

Autor: Tom W. Muir, Roodolph St. Pierre, Kristin Qian, Cigall Kadoch, Andrew R. D’Avino, Hayley J. Zullow, Neil T. Umbreit, Martin Filipovski, Evan B. Winter, Hyuk-Soo Seo, Matthew J. McBride, Jacob D. Jaffe, Sirano Dhe-Paganon, Hai T. Dao, Nazar Mashtalir, Alfredo M. Valencia
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Nature Structural & Molecular Biology
ISSN: 1545-9985
1545-9993
Popis: Interactions between chromatin-associated proteins and the histone landscape play major roles in dictating genome topology and gene expression. Cancer-specific fusion oncoproteins, which display unique chromatin localization patterns, often lack classical DNA-binding domains, presenting challenges in identifying mechanisms governing their site-specific chromatin targeting and function. Here we identify a minimal region of the human SS18-SSX fusion oncoprotein (the hallmark driver of synovial sarcoma) that mediates a direct interaction between the mSWI/SNF complex and the nucleosome acidic patch. This binding results in altered mSWI/SNF composition and nucleosome engagement, driving cancer-specific mSWI/SNF complex targeting and gene expression. Furthermore, the C-terminal region of SSX confers preferential affinity to repressed, H2AK119Ub-marked nucleosomes, underlying the selective targeting to polycomb-marked genomic regions and synovial sarcoma–specific dependency on PRC1 function. Together, our results describe a functional interplay between a key nucleosome binding hub and a histone modification that underlies the disease-specific recruitment of a major chromatin remodeling complex.
A combination of cell-based and biochemical approaches reveals how oncogenic fusion protein SS18-SSX directs BAF complexes to H2AK119Ub-modified nucleosomes to remodel chromatin at cancer-specific gene targets.
Databáze: OpenAIRE
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