Ribosomal DNA (rDNA) (rDNA)

Ribosomal DNA (rDNA) consists of tandemly repeated gene clusters that encode the precursor for the major ribosomal RNA components (18S, 5.8S, and 28S rRNA) (Drygin et al., 2011, Cancer Research). These clusters are transcribed by RNA polymerase I (Pol I) within the nucleolus and are characterized by an exceptionally high GC content, which facilitates the formation of G-quadruplex structures (Xu et al., 2017, Nature Communications). Because cancer cells require massive amounts of ribosomes to sustain rapid growth and division, they often exhibit hyperactivated Pol I transcription and enlarged nucleoli (Peltonen et al., 2014, Cancer Cell). Targeting the GC-rich rDNA sequences or the Pol I machinery has emerged as a potent strategy to selectively induce nucleolar stress and apoptosis in malignant cells (Mars et al., 2020, Nucleic Acids Research). Drugs like Pidnarulex (CX-5461) and BMH-21 act by stabilizing rDNA G-quadruplexes or intercalating into the DNA, respectively, which disrupts the transcription elongation process and triggers the degradation of Pol I subunits (Bruno et al., 2020, Nature Communications).

Other names

GC-rich ribosomal DNA45S ribosomal DNAPol I transcription unitsNucleolar organizer regionsrDNA

Drugs targeting this region primarily act by inhibiting RNA polymerase I (Pol I) transcription through several distinct mechanisms: stabilization of G-quadruplex structures within the GC-rich rDNA (e.g., CX-5461), which creates physical barriers to Pol I progression (Xu et al., 2017, Nature Communications); or direct intercalation into the rDNA (e.g., BMH-21), which leads to the dissociation and subsequent proteasomal degradation of the Pol I catalytic subunit RPA190 (Peltonen et al., 2014, Cancer Cell). These actions trigger a nucleolar stress response, often involving the release of ribosomal proteins that inhibit MDM2, thereby stabilizing p53 and inducing cell cycle arrest or apoptosis (Drygin et al., 2011, Cancer Research).