Molecular Mechanisms of RNA Polymerase I Transcription in Health and Disease: An Overview.

RNA polymerase I (Pol I) is a specialized eukaryotic enzyme responsible for transcribing ribosomal DNA into precursor rRNA, a process that initiates ribosome biogenesis and supports cellular growth, metabolism, and proliferation. Recent structural and mechanistic studies have revealed unique features of Pol I architecture that enable high transcriptional output and tight regulatory control. Pol I activity is dynamically regulated by signaling pathways, epigenetic mechanisms, and chromatin structure, integrating environmental and metabolic cues to fine-tune ribosome production. Dysregulation of Pol I transcription is associated with a wide spectrum of human diseases: hyperactivation is a hallmark of cancer, whereas loss-of-function mutations cause ribosomopathies, leukodystrophies, and neurodegenerative disorders through nucleolar stress. Targeted therapies, including small-molecule inhibitors and emerging peptide-based approaches, are expanding clinical strategies to modulate Pol I activity. Beyond its canonical role, Pol I contributes to genome stability, immune regulation, and host-pathogen interactions, broadening its therapeutic relevance. This review integrates structural, mechanistic, and disease perspectives on Pol I, highlighting how fundamental discoveries are informing the next generation of targeted interventions across oncology, neurodegeneration, developmental disorders, infection, and aging.