@article{82c43599aa6f419da0cd730aa17d4ba5,
title = "The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma",
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.",
author = "McBride, {Matthew J.} and Nazar Mashtalir and Winter, {Evan B.} and Dao, {Hai T.} and Martin Filipovski and D{\textquoteright}Avino, {Andrew R.} and Seo, {Hyuk Soo} and Umbreit, {Neil T.} and {St. Pierre}, Roodolph and Valencia, {Alfredo M.} and Kristin Qian and Zullow, {Hayley J.} and Jaffe, {Jacob D.} and Sirano Dhe-Paganon and Muir, {Tom W.} and Cigall Kadoch",
note = "Funding Information: We thank members of the Kadoch laboratory for critical feedback and advice. We thank members of the M.J.M. dissertation advisory committee, including S. Armstrong, D. Liu and M. Meyerson, for their guidance and mentorship throughout the development of this project. M.J.M. was supported by the Harvard Medical School GSAS Fellowship Program. N.M. is supported by NIH K99/R00 K99CA237855. H.T.D. was funded by a postdoctoral fellowship from the Jane Coffin Childs Memorial Fund. N.T.U. was supported in part by the Claudia Adams Barr Program for Innovative Cancer Research. This work was supported in part by awards from the NIH DP2 New Innovator Award 1DP2CA195762-01 (C.K.), the American Cancer Society Research Scholar Award RSG-14-051-01-DMC (C.K.), the Pew-Stewart Scholars in Cancer Research Grant (C.K.), Alex{\textquoteright}s Lemonade Stand Foundation {\textquoteleft}A Award{\textquoteright} (C.K.), NIH 1R01 CA237241-01 (C.K.), the NIH Cancer Moonshot FusOnc2 1U54 CA231638-01 (C.K.), NIH R37-GM086868 (T.W.M.) and NIH PO1-CA196539 (T.W.M.). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = sep,
day = "1",
doi = "10.1038/s41594-020-0466-9",
language = "English (US)",
volume = "27",
pages = "836--845",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "9",
}