The nucleosome acidic patch and H2A ubiquitination underlie mSWI/SNF recruitment in synovial sarcoma.
| Publication Type | Academic Article |
| Authors | McBride M, Mashtalir N, Winter E, Dao H, Filipovski M, D'Avino A, Seo H, Umbreit N, St Pierre R, Valencia A, Qian K, Zullow H, Jaffe J, Dhe-Paganon S, Muir T, Kadoch C |
| Journal | Nat Struct Mol Biol |
| Volume | 27 |
| Issue | 9 |
| Pagination | 836-845 |
| Date Published | 08/03/2020 |
| ISSN | 1545-9985 |
| Keywords | Chromosomal Proteins, Non-Histone, Histones, Neoplasm Proteins, Oncogene Proteins, Fusion, Proto-Oncogene Proteins, Repressor Proteins, Sarcoma, Synovial, Transcription Factors, Ubiquitins |
| 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. |
| DOI | 10.1038/s41594-020-0466-9 |
| PubMed ID | 32747783 |
| PubMed Central ID | PMC7714695 |