Selective Inhibition of rDNA Transcription by a Small- Molecule Peptide That Targets the Interface between RNA Polymerase I and Rrn3

The interface between the polymerase I–associated factor Rrn3 and the 43-kDa subunit of RNA polymerase I is essential totherecruitmentofPolItothepreinitiationcomplexontherDNApromoter.Insilicoanalysisidentified anevolutionarilyconserved22aminoacidpeptidewithinrpa43thatisbothnecessary andsufficienttomediatethe interaction between rpa43 and Rrn3. This peptide inhibited rDNA transcription in vitro, while a control peptide didnot.Todeterminetheeffectofthepeptideinculturedcells,thepeptidewascoupledtotheHIVTATpeptideto 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" resultsinthedeathoftumorcells.The22merisasmall-moleculeinhibitorofrDNAtranscriptionthatisspecificfor the interaction between Rrn3 and rpa43, as such it represents an original way to interfere with cell growth. Implications:These results demonstrate a potentially novel pharmaceutical target for the therapeutic treatment of cancer cells. Mol Cancer Res; 12(11); 1586–96. � 2014 AACR.