POLR1A encodes the catalytic core subunit of RNA polymerase I (Pol I), responsible for transcribing ribosomal DNA to produce 47S precursor rRNA, which is processed into mature 28S, 18S, and 5.8S rRNAs 1. As the largest Pol I subunit, POLR1A forms the active catalytic center with POLR1B/RPA2, catalyzing nucleotide addition via two coordinated Mg²⁺ ions and possessing proofreading activity through interaction with POLR1H/RPA12 [UniProt]. During transcription, Pol I progresses through initiation, elongation, and termination stages, with high processivity and formation of characteristic 'Miller tree' structures in rDNA regions [UniProt]. POLR1A mutations cause ribosomopathies with tissue-specific manifestations, particularly affecting craniofacial development 23. Heterozygous variants cause acrofacial dysostosis and related anomalies through cell-autonomous apoptosis in neural crest cells and cardiac lineages due to impaired ribosome biogenesis 2. Biallelic POLR1A mutations cause leukodystrophy with progressive neurological deficits, aberrant rRNA processing, and endoplasmic reticulum stress 1. The craniofacial vulnerability reflects high Pol I expression in neural crest progenitors, which depend on elevated rRNA synthesis and become particularly sensitive to synthesis defects 3. Beyond development, POLR1A supports ferroptosis resistance in cancer via nucleolar-mitochondrial signaling involving TFAM-mediated mitophagy and iron homeostasis, offering therapeutic targets through Pol I inhibition 4.