{"doi":"10.1101/gad.345454.120","title":"<i>RAD21</i> is a driver of chromosome 8 gain in Ewing sarcoma to mitigate replication stress","abstract":"Aneuploidy, defined as whole-chromosome gain or loss, causes cellular stress but, paradoxically, is a frequent occurrence in cancers. Here, we investigate why ∼50% of Ewing sarcomas, driven by the EWS-FLI1 fusion oncogene, harbor chromosome 8 gains. Expression of the EWS-FLI1 fusion in primary cells causes replication stress that can result in cellular senescence. Using an evolution approach, we show that trisomy 8 mitigates EWS-FLI1 -induced replication stress through gain of a copy of RAD21. Low-level ectopic expression of RAD21 is sufficient to dampen replication stress and improve proliferation in EWS-FLI1 -expressing cells. Conversely, deleting one copy in trisomy 8 cells largely neutralizes the fitness benefit of chromosome 8 gain and reduces tumorgenicity of a Ewing sarcoma cancer cell line in soft agar assays. We propose that RAD21 promotes tumorigenesis through single gene copy gain. Such genes may explain some recurrent aneuploidies in cancer.","journal":"Genes & Development","year":2021,"id":212925,"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":58,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":612852,"name":"Duanduan Ma","orcid":"0000-0002-4753-0813","position":1,"is_corresponding":false},{"id":804816,"name":"James V. Parsons","orcid":null,"position":2,"is_corresponding":false},{"id":273092,"name":"John Replogle","orcid":null,"position":3,"is_corresponding":false},{"id":7765,"name":"James F. Amatruda","orcid":"0000-0002-9901-2137","position":4,"is_corresponding":false},{"id":54226,"name":"Charles A. Whittaker","orcid":"0000-0002-2400-0094","position":5,"is_corresponding":false},{"id":268862,"name":"Kimberly Stegmaier","orcid":"0000-0003-0218-7895","position":6,"is_corresponding":false},{"id":14822,"name":"Angelika Amon","orcid":"0000-0001-9837-0314","position":7,"is_corresponding":false},{"id":804054,"name":"Xiaofeng A. Su","orcid":"0000-0003-4960-6372","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T23:52:31.378994Z","pmid":"33766983","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":[]}