title: Selective inhibition of rDNA transcription by a small-molecule peptide that targets the interface between RNA polymerase I and Rrn3.
abstract: The interface between the polymerase I-associated factor Rrn3 and the 43-kDa subunit of RNA polymerase I is essential to the recruitment of Pol I to the preinitiation complex on the rDNA promoter. In silico analysis identified an evolutionarily conserved 22 amino acid peptide within rpa43 that is both necessary and sufficient to mediate the interaction between rpa43 and Rrn3. This peptide inhibited rDNA transcription in vitro, while a control peptide did not. To determine the effect of the peptide in cultured cells, the peptide was coupled to the HIV TAT peptide to facilitate transduction into cells. The wild-type peptide, but not control peptides, inhibited Pol I transcription and cell division. In addition, the peptide induced cell death, consistent with other observations that "nucleolar stress" results in the death of tumor cells. The 22mer is a small-molecule inhibitor of rDNA transcription that is specific for the interaction between Rrn3 and rpa43, as such it represents an original way to interfere with cell growth.
  
  
  CONCLUSIONS
  These results demonstrate a potentially novel pharmaceutical target for the therapeutic treatment of cancer cells.
authors.affiliation: Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma.
authors.forename: Katrina
authors.initials: K
authors.lastname: Rothblum
authors.affiliation: South Cove Community Health Care Center, Quincy, Massachusetts.
authors.forename: Qiyue
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Penrod
authors.affiliation: Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma. lrothblu@ouhsc.edu.
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Rothblum
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004275:DNA, Ribosomal / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology*; D010641:Phenotype; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012318:RNA Polymerase I / Q000378:metabolism*; D051381:Rats; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014161:Transduction, Genetic; D020798:Two-Hybrid System Techniques
chemical_list: D004275:DNA, Ribosomal; D004268:DNA-Binding Proteins; D010455:Peptides; D035463:Pol1 Transcription Initiation Complex Proteins; C428423:RRN3 protein, human; C491074:Rrn3 protein, mouse; D054852:Small Molecule Libraries; D012318:RNA Polymerase I