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

TitleThe nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma.
Publication TypeJournal Article
Year of Publication2020
AuthorsMcBride, MJ, Mashtalir, N, Winter, EB, Dao, HT, Filipovski, M, D'Avino, AR, Seo, H-S, Umbreit, NT, St Pierre, R, Valencia, AM, Qian, K, Zullow, HJ, Jaffe, JD, Dhe-Paganon, S, Muir, TW, Kadoch, C
JournalNat Struct Mol Biol
Volume27
Issue9
Pagination836-845
Date Published2020 09
ISSN1545-9985
KeywordsCell Line, Tumor, Chromosomal Proteins, Non-Histone, HEK293 Cells, Histones, Humans, Models, Molecular, Neoplasm Proteins, Nucleosomes, Oncogene Proteins, Fusion, Protein Conformation, Proto-Oncogene Proteins, Repressor Proteins, Sarcoma, Synovial, Transcription Factors, Ubiquitination, Ubiquitins
Abstract

<p>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.</p>

DOI10.1038/s41594-020-0466-9
Alternate JournalNat Struct Mol Biol
PubMed ID32747783
PubMed Central IDPMC7714695
Grant ListR01 CA237241 / CA / NCI NIH HHS / United States
K99 CA237855 / CA / NCI NIH HHS / United States
P01 CA196539 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
DP2 CA195762 / CA / NCI NIH HHS / United States
U54 CA231638 / CA / NCI NIH HHS / United States
R37 GM086868 / GM / NIGMS NIH HHS / United States