9DWU

CoREST complex bound to U2AF2

Summary for 9DWU

• Entry DOI: 10.2210/pdb9dwu/pdb
• EMDB information: 47265
• Descriptor: Lysine-specific histone demethylase 1A, REST corepressor 1, Splicing factor U2AF 65 kDa subunit (3 entities in total)
• Functional Keywords: rna, splicing, melanoma, epigenetics, gene regulation
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 90444.47

Authors

Hicks, C.W.,Alani, R.M. (deposition date: 2024-10-10, release date: 2025-01-08)

Primary citation

Fisher, R.J.,Park, K.,Lee, K.,Pinjusic, K.,Vanasse, A.,Ennis, C.S.,Ficcaro, S.,Marto, J.,Stransky, S.,Duke-Cohan, J.,Geethadevi, A.,Raabe, E.,Sidoli, S.,Hicks, C.W.,Keskin, D.B.,Wu, C.J.,Cole, P.A.,Alani, R.M.
CoREST Complex Inhibition Alters RNA Splicing to Promote Neoantigen Expression and Enhance Tumor Immunity.
Biorxiv, 2024

PubMed Abstract: Epigenetic complexes tightly regulate gene expression and colocalize with RNA splicing machinery; however, the consequences of these interactions are uncertain. Here, we identify unique interactions of the CoREST repressor complex with RNA splicing factors and their functional consequences in tumorigenesis. Using mass spectrometry, in vivo binding assays, and cryo-EM we find that CoREST complex-splicing factor interactions are direct and perturbed by the CoREST complex inhibitor, corin, leading to extensive changes in RNA splicing in melanoma and other malignancies. Using predictive machine learning models and MHC IP-MS, we identify thousands of corin-induced neopeptides derived from unannotated splice sites which generate immunogenic splice-neoantigens. Furthermore, corin reactivates the response to immune checkpoint blockade and promotes dramatic expansion of cytotoxic T cells in an immune cold melanoma model. CoREST complex inhibition thus represents a unique therapeutic opportunity in cancer which creates tumor-associated neoantigens that enhance the immunogenicity of current therapeutics.

PubMed: 39713349
DOI: 10.1101/2024.12.12.627852

Experimental method

ELECTRON MICROSCOPY (5.14 Å)