Title | The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | McBride, 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 |
Journal | Nat Struct Mol Biol |
Volume | 27 |
Issue | 9 |
Pagination | 836-845 |
Date Published | 2020 Sep |
ISSN | 1545-9985 |
Keywords | Cell 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> |
DOI | 10.1038/s41594-020-0466-9 |
Alternate Journal | Nat Struct Mol Biol |
PubMed ID | 32747783 |
PubMed Central ID | PMC7714695 |
Grant List | R01 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 |