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Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa (TOP2A) inhibitor etoposide in lung cancer. Because heat shock conditions (HS) protect cells against the toxicity of etoposide, and SatIII is significantly induced under HS, we hypothesized that the protective effect could be traced back to SatIII. Using genome methylation profiles of patient-derived xenograft mouse models we show that the epigenetic modification of the <jats:italic>SatIII<\/jats:italic> DNA locus and the resulting SatIII expression predict chemotherapy resistance. In response to stress, SatIII recruits TOP2A to nuclear stress bodies, which protects TOP2A from a complex formation with etoposide and results in decreased DNA damage after treatment. We show that BRD4 inhibitors reduce the expression of SatIII, restoring etoposide sensitivity.<\/jats:p>","DOI":"10.1038\/s41419-021-03810-9","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T08:03:01Z","timestamp":1621843381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pericentromeric Satellite III transcripts induce etoposide resistance"],"prefix":"10.1038","volume":"12","author":[{"given":"Julian","family":"Kanne","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Hussong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3390-0051","authenticated-orcid":false,"given":"J\u00f6rg","family":"Isensee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1lvaro","family":"Mu\u00f1oz-L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Wolffgramm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"He\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4676-8870","authenticated-orcid":false,"given":"Christina","family":"Grimm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Bessonov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Meder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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The establishment of these PDX models from NSCLC patients was approved (EA3\/001\/06) by the local ethical review committee (Charit\u00e9 Berlin). Written informed consent to participate in the study was obtained from all patients. The use of clinical data and patient\u2019s material was approved by the institutional review board of the ELK Berlin Chest Hospital. All mice used in the study were handled in accordance with the Guidelines for the Welfare and Use of Animals in Cancer Research<sup>53<\/sup>. Their use was approved by the local responsible authorities (approval no. G 0030\/15), according to the German Animal Protection Law.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}},{"value":"H.C.R. received consulting and lecture fees from Abbvie, Astra-Zeneca, Vertex, and Merck. H.C.R. received research funding from Gilead Pharmaceuticals. H.C.R. is a co-founder of CDL Therapeutics GmbH. No potential conflicts of interest were disclosed by the other authors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"530"}}