RNA polymerase I transcriptional machinery (Pol I)

The RNA polymerase I (Pol I) transcriptional machinery is a specialized multi-protein complex responsible for the synthesis of the 45S precursor ribosomal RNA (pre-rRNA), which is the rate-limiting step in ribosome biogenesis (Hannan et al., 2013, Nature Reviews Drug Discovery). This machinery consists of the 14-subunit Pol I enzyme itself along with essential transcription factors such as the Upstream Binding Factor (UBF) and the Selectivity Factor 1 (SL1) complex (UniProt Consortium, 2023). In healthy cells, Pol I activity is tightly regulated to match the metabolic demands of the cell; however, in many cancers, this machinery is hyperactivated by oncogenic signaling pathways like c-Myc and PI3K/AKT to support rapid cell proliferation (Bywater et al., 2012, Cancer Cell). Targeting the Pol I machinery has emerged as a potent strategy in oncology, as cancer cells are often addicted to high levels of ribosome production (Drygin et al., 2011, Cancer Research). Small molecule inhibitors like CX-5461 (Pidnarulex) and BMH-21 work by disrupting the assembly of the transcription initiation complex or inducing the degradation of Pol I subunits, respectively (Peltonen et al., 2014, Cancer Cell). These interventions trigger nucleolar stress, which stabilizes p53 and induces apoptosis specifically in malignant cells while sparing normal cells to a degree (Hannan et al., 2013, Nature Reviews Drug Discovery).

Other names

RNA polymerase I complexPol I transcription apparatusrDNA transcription machineryRNA polymerase I holoenzyme

Inhibition of ribosomal DNA (rDNA) transcription by preventing the assembly of the initiation complex (e.g., blocking SL1 binding) or causing the proteasomal degradation of the large catalytic subunit (RPA190), leading to nucleolar stress and p53-mediated apoptosis (Drygin et al., 2011; Peltonen et al., 2014).