{"doi":"10.64898/2026.01.29.702547","title":"Decoding the\n                  <i>MYC</i>\n                  locus reveals a druggable ultraconserved RNA element","abstract":"<jats:title>ABSTRACT</jats:title>\n                <jats:p>\n                  The human genome is dominated by noncoding sequences, most of which are poorly conserved across species. How genetic information is distributed between coding and noncoding regions remains a fundamental unresolved question. Using CRISPR saturation mutagenesis at base-pair resolution, we mapped the functional fitness landscape of the 10-kb human\n                  <jats:italic>MYC</jats:italic>\n                  locus with a near-PAMless, high-fidelity SpRY-Cas9. This unbiased interrogation revealed that the majority (67%) of functionally essential base-pairs in this locus are noncoding. Paradoxically, the phenotypic impact of noncoding sequences correlates inversely with evolutionary conservation, driven in part by rapidly diverging cis-regulatory DNA elements that remain functionally constrained in humans. Within this landscape, we identified an ultraconserved RNA element in the 3’ untranslated region (UTR) that is indispensable for MYC-dependent cancer cells. Remarkably, steric-blocking antisense oligos targeting this RNA element selectively eliminate MYC-addicted cancer cells by suppressing MYC function without reducing MYC abundance. Mechanistically, this 3′ UTR element promotes perinuclear localization of\n                  <jats:italic>MYC</jats:italic>\n                  mRNA and efficient nuclear import of the short-lived MYC protein, enabling its function as a nuclear transcription factor. Together, these findings highlight noncoding sequences as major carriers of functional genetic information, provide a comprehensive fitness map of the\n                  <jats:italic>MYC</jats:italic>\n                  locus, and uncover a therapeutically actionable RNA element that disables MYC-driven cancer.\n                </jats:p>","journal":null,"year":2026,"id":8774,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2026-01-30","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":75500,"name":"Feiyue Yang","orcid":"0009-0009-1860-288X","position":1,"is_corresponding":false},{"id":75501,"name":"FNU Tala","orcid":"0009-0006-4240-4099","position":2,"is_corresponding":false},{"id":75502,"name":"Wesley Huang","orcid":null,"position":3,"is_corresponding":false},{"id":75503,"name":"Alexis O. Aparicio","orcid":"0000-0002-1107-2718","position":4,"is_corresponding":false},{"id":75504,"name":"Colin H. Kalicki","orcid":"0009-0002-6353-8492","position":5,"is_corresponding":false},{"id":75505,"name":"Aditi Trehan","orcid":null,"position":6,"is_corresponding":false},{"id":75506,"name":"Michael R. Murphy","orcid":"0000-0002-0470-5791","position":7,"is_corresponding":false},{"id":75507,"name":"Esther R. Rotlevi","orcid":"0000-0001-8996-3169","position":8,"is_corresponding":false},{"id":75508,"name":"Linqing Xing","orcid":"0009-0003-6087-202X","position":9,"is_corresponding":false},{"id":75509,"name":"Muredach P. Reilly","orcid":"0000-0002-3035-9386","position":10,"is_corresponding":false},{"id":75510,"name":"Jianwen Que","orcid":"0000-0002-6540-6701","position":11,"is_corresponding":false},{"id":75511,"name":"Xuebing Wu","orcid":"0000-0003-0369-5269","position":12,"is_corresponding":false},{"id":75512,"name":"Tala FNU","orcid":null,"position":13,"is_corresponding":false},{"id":75513,"name":"Colin Kalicki","orcid":null,"position":14,"is_corresponding":false},{"id":75514,"name":"Onur Özer","orcid":"0000-0003-2284-6181","position":15,"is_corresponding":false},{"id":75499,"name":"Peiguo Shi","orcid":"0000-0001-7177-8336","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","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":[]}