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JP-1302 is a blood-brain barrier-penetrant 9-anilinoacridine derivative developed as an \u03b1\n                    <jats:sub>2C<\/jats:sub>\n                    -adrenergic receptor antagonist, but also recently identified as an RNA Pol II inhibitor at micromolar concentrations (~5\u201310\u2009\u03bcM). Here we show that JP-1302 also suppresses Pol I-driven 47S pre-rRNA synthesis at submicromolar-to-low-micromolar concentrations, evidenced by loss of nascent EU-labelled rRNA and reduced activity of an rDNA promoter-driven luciferase reporter. This was accompanied by preferential proteasome-dependent degradation of the Pol I catalytic subunit POLR1A, independent of \u03b1\n                    <jats:sub>2C<\/jats:sub>\n                    -adrenergic receptor signalling, displacement of POLR1A from the rDNA promoter and progressive disruption of nucleolar morphology. Growth inhibitory IC\n                    <jats:sub>50<\/jats:sub>\n                    values across a panel of normal and cancer cell lines, including glioblastoma, ranged from submicromolar to low micromolar. Nucleolar stress stabilised p53 and induced p21 expression at low-to-intermediate concentrations, without evidence of DNA damage at these doses (no \u03b3H2AX increase at concentrations sufficient to abrogate Pol I transcription). Interestingly, p53-null and p53-wild type cells showed comparable S-phase depletion in response to JP-1302. At higher concentrations, JP-1302 additionally caused covalent trapping of TOP2A\/TOP2B, accompanied by delayed \u03b3H2AX induction, and enrichment of the FACT subunits SSRP1 and SPT16 on chromatin. Together, these findings identify JP-1302 as a pharmacologically distinct inhibitor of ribosome biogenesis with broader, dose-dependent chromatin-disruptive activity.\n                  <\/jats:p>","DOI":"10.1038\/s41420-026-03381-8","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:13:20Z","timestamp":1790788400000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["JP-1302 inhibits RNA polymerase I transcription and induces nucleolar stress in cancer cell lines"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2221-1840","authenticated-orcid":false,"given":"Sheetanshu","family":"Saproo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9156-9996","authenticated-orcid":false,"given":"Styliani","family":"Papadaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johana","family":"Fernandez-Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinky","family":"Sultana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8690-2010","authenticated-orcid":false,"given":"Dimitris C.","family":"Kanellis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2013-7525","authenticated-orcid":false,"given":"Jiri","family":"Bartek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1148-8497","authenticated-orcid":false,"given":"Mikael S.","family":"Lindstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"3381_CR1","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/nrc.2017.104","volume":"18","author":"J Pelletier","year":"2018","unstructured":"Pelletier J, Thomas G, Volarevic S. 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