{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:24:36Z","timestamp":1786944276644,"version":"build-2736575974"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hyperactivated RNA polymerase I (Pol I)-driven ribosomal DNA (rDNA) transcription sustains malignant growth and chemotherapy tolerance in lung adenocarcinoma (LUAD). Genotoxic chemotherapeutics such as doxorubicin and cisplatin preferentially damage rDNA by inducing DNA-protein crosslinks (DPCs), yet how tumor cells preserve Pol I transcriptional output under this damage remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated SPRTN function in LUAD using complementary approaches spanning molecular, cellular, and\n                      <jats:italic>in vivo<\/jats:italic>\n                      levels, including DNA-protein crosslink isolation, chromatin immunoprecipitation, nascent RNA synthesis assays, apoptosis and invasion assays in SPRTN loss- and gain-of-function cell models, mouse xenograft studies, and transcriptomic analysis of clinical LUAD datasets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      SPRTN was enriched at the rDNA promoter, limited basal DPC accumulation, sustained Pol I transcriptional output, suppressed the p53-p21 nucleolar stress checkpoint, and promoted Pol I-dependent proliferation. Under doxorubicin or cisplatin treatment, SPRTN was recruited to G-quadruplex-rich rDNA promoters, a process associated with PARP-1 co-recruitment, and facilitated DPC resolution and transcriptional recovery. Catalytically inactive SPRTN failed to resolve rDNA-DPCs and restore Pol I output under both basal and drug-treated conditions. Doxorubicin- and cisplatin-resistant LUAD cells exhibited elevated SPRTN expression and enhanced rRNA synthesis relative to parental cells. SPRTN knockdown increased apoptotic response to doxorubicin and cisplatin, and co-inhibition of SPRTN and Pol I additively induced apoptosis in both parental and resistant cells. SPRTN further promoted Pol I-dependent migration and invasion. Transcriptomically, SPRTN was upregulated in LUAD, correlated with advanced disease stage and reduced overall survival, and was transcriptionally activated by ZEB1 and post-transcriptionally repressed by miR-195-5p.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , SPRTN silencing reduced tumor burden and suppressed Pol I transcription, with further reduction upon doxorubicin treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings establish SPRTN as an rDNA-associated repair factor that couples genotoxic damage resolution to Pol I transcriptional resilience, defining the SPRTN-Pol I axis as a determinant of nucleolar homeostasis and therapeutic vulnerability in lung adenocarcinoma.<\/jats:p>\n                  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