{"doi":"10.1101/2023.08.01.551488","title":"<i>XRN1</i> deletion induces PKR-dependent cell lethality in interferon-activated cancer cells","abstract":"Summary Emerging data suggest that induction of viral mimicry responses through activation of double-stranded RNA (dsRNA) sensors in cancer cells is a promising therapeutic strategy. One approach to induce viral mimicry is to target molecular regulators of dsRNA sensing pathways. Here, we show that the exoribonuclease XRN1 is a negative regulator of the dsRNA sensor protein kinase R (PKR) in cancer cells with high interferon-stimulated gene (ISG) expression. XRN1 deletion causes PKR activation and consequent cancer cell lethality. Disruption of interferon signaling with the JAK1/2 inhibitor ruxolitinib can decrease cellular PKR levels and rescue sensitivity to XRN1 deletion. Conversely, interferon-β stimulation can increase PKR levels and induce sensitivity to XRN1 inactivation. Lastly, XRN1 deletion causes accumulation of endogenous complementary sense/anti-sense RNAs, which may represent candidate PKR ligands. Our data demonstrate how XRN1 regulates PKR and nominate XRN1 as a potential therapeutic target in cancer cells with an activated interferon cell state.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":400300,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1176542,"name":"Meng Zhou","orcid":"0000-0001-5187-9084","position":1,"is_corresponding":false},{"id":1176543,"name":"Akansha Gupta","orcid":"0000-0002-4590-8296","position":2,"is_corresponding":false},{"id":1176834,"name":"Patrick Zhuang","orcid":null,"position":3,"is_corresponding":false},{"id":1176835,"name":"Alyssa R. Fishbein","orcid":null,"position":4,"is_corresponding":false},{"id":1176836,"name":"Hope Y. Wei","orcid":null,"position":5,"is_corresponding":false},{"id":683341,"name":"Zhouwei Zhang","orcid":"0000-0001-6362-9031","position":6,"is_corresponding":false},{"id":13344,"name":"Andrew D. Cherniack","orcid":"0000-0003-0470-0111","position":7,"is_corresponding":false},{"id":107871,"name":"Matthew Meyerson","orcid":"0000-0002-9133-8108","position":8,"is_corresponding":false},{"id":1176541,"name":"Tao Zou","orcid":"0000-0003-4320-1534","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T01:20:00.023537Z","pmid":"37577567","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":[]}