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

DNA-directed RNA polymerases I, II, and III (historically known as RNA polymerases A, B, and C) are the three essential multi-subunit enzyme complexes responsible for all nuclear transcription in eukaryotes [1, 9]. RNA polymerase I (Pol I) is specialized for the synthesis of the 45S pre-ribosomal RNA (rRNA) in the nucleolus, a rate-limiting step for ribosome biogenesis that is frequently hyperactivated in cancer cells to support rapid growth [6]. RNA polymerase II (Pol II) transcribes all protein-coding genes into messenger RNA (mRNA) and is the primary target for many transcriptional regulatory factors and certain toxins like alpha-amanitin [2, 4]. RNA polymerase III (Pol III) synthesizes essential small RNAs, including transfer RNA (tRNA) and 5S rRNA [1, 9]. These enzymes are increasingly recognized as therapeutic targets, particularly in oncology, where inhibitors like CX-5461 and BMH-21 are designed to exploit the transcriptional addiction of malignant cells [6, 10]. However, because these polymerases are fundamental to the survival of all cells, developing drugs with a sufficient therapeutic window remains a significant challenge [2, 6].

Other names

RNA polymerase ARNA polymerase BRNA polymerase CPol IPol IIPol IIIRNAP IRNAP IIRNAP IIIEukaryotic RNA polymerasesDNA-directed RNA polymerase IDNA-directed RNA polymerase IIDNA-directed RNA polymerase III

Inhibition of RNA synthesis through various mechanisms, including blocking the catalytic active site, preventing promoter escape, inducing polymerase subunit degradation, or interfering with essential transcription factor recruitment [2, 6, 10].