title: Cisplatin inhibits synthesis of ribosomal RNA in vivo.
abstract: Cis -diammininedichloroplatinum(II) (cisplatin or cis -DDP) is a DNA-damaging agent that is widely used in cancer chemotherapy. Cisplatin crosslinks DNA and the resulting adducts interact with proteins that contain high-mobility-group (HMG) domains, such as UBF(upstream binding factor). UBF is a transcription factor that binds to the promoter of ribosomal RNA (rRNA) genes thereby supporting initiation of transcription by RNA polymerase I. Here we report that cisplatin causes a redistribution of UBF in the nucleolus of human cells, similar to that observed after inhibition of rRNA synthesis. A similar redistribution was observed for the major components of the rRNA transcription machinery, namely TBP, TAFIs and RNA polymerase I. Furthermore, we provide for the first time direct in vivo evidence that cisplatin blocks synthesis of rRNA, while activity of RNA polymerase II continues to be detected throughout the nucleus. The clinically ineffective trans isomer (trans -DDP) does not alter the localization of either UBF or other components of the RNA polymerase I transcription machinery. These results suggest that disruption of rRNA synthesis, which is stimulated in proliferating cells, plays an important role in the clinical success of cisplatin.
authors.affiliation: Institute of Histology and Embryology, Faculty of Medicine, University of Lisbon, 1699 Lisboa Codex, Portugal.
authors.forename: P
authors.initials: P
authors.lastname: Jordan
authors.forename: M
authors.initials: M
authors.lastname: Carmo-Fonseca
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D025901:Carboxypeptidase B2; D002268:Carboxypeptidases / Q000378:metabolism; D002466:Cell Nucleolus / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D035463:Pol1 Transcription Initiation Complex Proteins; D012318:RNA Polymerase I / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D035181:TATA-Box Binding Protein; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; D035181:TATA-Box Binding Protein; D014157:Transcription Factors; C063844:transcription factor UBF; C034697:transplatin; D012319:RNA Polymerase II; D012318:RNA Polymerase I; D002268:Carboxypeptidases; D025901:Carboxypeptidase B2; D002945:Cisplatin