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A Cryptic Basic Groove formed by Ubiquitin and Histone H3 Mediates the Selective Recognition of H2AK119Ub Nucleosomes by Synovial Sarcoma X Breakpoint 1 Protein

ABSTRACT: The cancer-specific fusion oncoprotein SS18-SSX1 disturbs chromatin accessibility by hijacking the chromatin-remodeling BAF complex from the promoters or enhancers to the H2AK119Ub-marked polycomb-repressed chromatin regions. Relocation of the BAF complex was achieved through selective recognition of the H2AK119Ub nucleosomes by the synovial sarcoma X breakpoint 1 protein SSX1, which neither has a ubiquitin (Ub)-binding domain nor binds to free Ub. To elucidate the mechanism by which SSX1 selectively recognizes H2AK119Ub nucleosomes, here we report the cryo-EM structure of SSX1 bound to H2AK119Ub nucleosomes at a resolution of 3.1 Å. The structure reveals that the SSX1 N-terminal basic region (residues W164, R167, L168, R169) is anchored to the H2A/H2B acidic patch, while the aromatic amino acid (residue Y177) in the middle of SSX1 interacts with the hydrophobic pocket formed by the H2A α2 and α3 helixes. Ub recognition by SSX1 is unique and depends on a cryptic basic groove formed by H3 (residues R49, R52, K56) and the Ub motif (residues R42, R72, R74) on the H2AK119 site. Our results describe a novel mode of site-specific ubiquitinated nucleosome recognition that underlies the specific hijacking of the BAF complex to polycomb regions by SS18-SSX1 in synovial sarcoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236811 | GEO | 2023/09/04

REPOSITORIES: GEO

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