DNA-directed RNA polymerase (I, II, and III) (RNAP I/II/III)

RNA polymerase I, II, and III are the three essential multi-subunit enzyme complexes responsible for nuclear transcription in eukaryotes (UniProt, 2024). RNA polymerase I synthesizes the precursor of ribosomal RNA (rRNA), which is the rate-limiting step for ribosome biogenesis and cell growth (Khatter et al., 2015, PMID: 25533018). RNA polymerase II transcribes all protein-coding genes into messenger RNA (mRNA) and is a primary target for regulating cell identity and stress responses (Wikipedia, 2024). RNA polymerase III produces small functional RNAs, including transfer RNA (tRNA) and 5S rRNA, which are vital for protein translation (Drygin et al., 2010, PMID: 20055702). In many cancers, the activity of these polymerases is significantly upregulated to support the metabolic demands of rapid proliferation (Khatter et al., 2015). Therapeutic agents like dactinomycin and lurbinectedin interact with these complexes or their DNA templates to inhibit RNA synthesis and induce apoptosis in tumor cells (FDA, 2020). Selective inhibitors of RNA polymerase I, such as CX-5461, are being developed to trigger nucleolar stress as a novel anti-cancer strategy (PMID: 28137913). However, because these enzymes are fundamental to the survival of all eukaryotic cells, drugs targeting them often face challenges related to systemic toxicity and a narrow therapeutic window (Drygin et al., 2010).

Other names

RNA polymeraseDNA-directed RNA polymeraseRNAPPol I, II, and IIIDNA-dependent RNA polymerase

Inhibition of DNA-directed RNA synthesis by blocking the elongation or initiation of transcription, often through DNA intercalation, direct binding to polymerase subunits, or inducing the degradation of the catalytic subunit (e.g., RPB1).