{"doi":"10.1101/2020.03.11.987750","title":"Disruption of oncogenic targeting by ISWI via phosphorylation of a prion-like domain","abstract":"Summary Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis and the effect of cancer therapies on their function are not well understood. Here, we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable radiation sensitivity of myxoid liposarcomas. We identified novel interactions between FUS-CHOP and chromatin remodeling complexes that regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, co-localizes with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylate the prion-like domain of FUS-CHOP to impede these protein-protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupts oncogenic targeting of chromatin remodelers required for FUS-CHOP-driven sarcomagenesis. Significance Prion-like domains translocated in cancer have been shown to drive global epigenetic changes that are oncogenic. However, some translocation-driven cancers exhibit dramatic clinical responses to therapy, though the mechanism for these responses are not well-understood. Here we show that ionizing radiation can disrupt oncogenic interactions between a fusion oncoprotein and a chromatin remodeling complex, ISWI. This mechanism of disruption links phosphorylation of the prion-like domain in an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":124702,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":452274,"name":"Joseph P. Foster","orcid":null,"position":1,"is_corresponding":false},{"id":569879,"name":"Ian C. Lock","orcid":"0000-0001-8247-4514","position":2,"is_corresponding":false},{"id":569880,"name":"Nathan H. Leisenring","orcid":"0000-0002-3404-4226","position":3,"is_corresponding":false},{"id":569881,"name":"Andrea R. Daniel","orcid":"0000-0003-2186-5911","position":4,"is_corresponding":false},{"id":569882,"name":"Warren Floyd","orcid":"0000-0003-4371-8453","position":5,"is_corresponding":false},{"id":473499,"name":"Eric S. Xu","orcid":"0000-0001-9933-9386","position":6,"is_corresponding":false},{"id":13386,"name":"Ian J. Davis","orcid":"0000-0002-1552-0960","position":7,"is_corresponding":false},{"id":334422,"name":"David G. Kirsch","orcid":"0000-0002-2086-205X","position":8,"is_corresponding":false},{"id":569878,"name":"Mark Chen","orcid":"0000-0001-5616-9321","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-18T23:15:11.632153Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}