3 years ago

Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain

Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain
Rémi Buisson, Liliane C. Broye, Mary E. Awad, Miguel N. Rivera, Gaylor Boulay, Angela Volorio, Shruthi Rengarajan, Cigall Kadoch, Sowmya Iyer, Lee Zou, Ivan Stamenkovic, Beverly Naigles, Nicolo Riggi, Matthew J. McBride, Gabriel J. Sandoval

Summary

Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.

Publisher URL: http://www.cell.com/cell/fulltext/S0092-8674(17)30872-3

DOI: 10.1016/j.cell.2017.07.036

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