DNA-directed RNA polymerase I subunit A (POLR1A) (POLR1A)

DNA-directed RNA polymerase I subunit A, encoded by the POLR1A gene, is the largest catalytic subunit of the RNA polymerase I (Pol I) complex, which is exclusively responsible for the transcription of the 45S ribosomal RNA (rRNA) precursor [1]. This process is the rate-limiting step in ribosome biogenesis, a pathway that is frequently hyperactivated in cancer cells to support the high protein synthesis demands of rapid proliferation [2]. Consequently, RPA1 and the Pol I complex have emerged as significant therapeutic targets in oncology, particularly for "ribosome-addicted" tumors. Small molecule inhibitors such as CX-5461 (Pidnarulex) and BMH-21 disrupt Pol I transcription, triggering nucleolar stress and the activation of p53-mediated cell death [2, 3]. Beyond its role in malignancy, germline mutations in the POLR1A gene are associated with ribosomopathies like Treacher Collins syndrome, which manifest as severe craniofacial developmental defects [4]. Therapeutic challenges in targeting this molecule include managing clinical toxicities such as photosensitivity and hematological effects, as well as ensuring high selectivity to avoid interfering with RNA polymerase II or III [2]. [1] UniProt (P49069); [2] Drygin D, et al. (2011) Cancer Research; [3] Peltonen K, et al. (2014) Cancer Cell; [4] Sanchez E, et al. (2015) Nature Communications.

Other names

DNA-directed RNA polymerase I subunit RPA1RNA polymerase I subunit ARPA194A190RPA1

Inhibition of RNA polymerase I-mediated transcription of ribosomal RNA (rRNA), leading to nucleolar stress and p53-dependent apoptosis.