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

Matthew J. McBride, Nazar Mashtalir, Evan B. Winter, Hai T. Dao, Martin Filipovski, Andrew R. D’Avino, Hyuk Soo Seo, Neil T. Umbreit, Roodolph St. Pierre, Alfredo M. Valencia, Kristin Qian, Hayley J. Zullow, Jacob D. Jaffe, Sirano Dhe-Paganon, Tom W. Muir, Cigall Kadoch

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)836-845
Number of pages10
JournalNature Structural and Molecular Biology
Volume27
Issue number9
DOIs
StatePublished - Sep 1 2020

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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    McBride, M. J., Mashtalir, N., Winter, E. B., Dao, H. T., Filipovski, M., D’Avino, A. R., Seo, H. S., Umbreit, N. T., St. Pierre, R., Valencia, A. M., Qian, K., Zullow, H. J., Jaffe, J. D., Dhe-Paganon, S., Muir, T. W., & Kadoch, C. (2020). The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma. Nature Structural and Molecular Biology, 27(9), 836-845. https://doi.org/10.1038/s41594-020-0466-9