POLR2E encodes a shared subunit of RNA polymerases I, II, and III, serving as a fundamental component of the transcription machinery. As part of the lower jaw structure surrounding the central cleft in Pol II, POLR2E directly participates in DNA template binding and coordination during transcription initiation, elongation, and termination across diverse gene classes including mRNA precursors, ribosomal RNAs, and transfer RNAs [UniProt/GO annotations]. Functionally, POLR2E is essential for transcription initiation at Pol I, II, and III promoters, with roles in nucleoplasm localization and protein stabilization within the core polymerase complexes. Clinically, the rs3787016 polymorphism in POLR2E has emerged as a significant genetic risk factor across multiple cancer types. This single nucleotide polymorphism associates with increased cancer susceptibility in prostate 1, breast, cervical 2, gastric 3, esophageal 4, papillary thyroid 5, and liver cancers 1. Meta-analyses confirm rs3787016 contributes to overall cancer predisposition 6. In gastric cancer, the AA genotype predicts worse prognosis with advanced TNM staging and reduced overall survival 3. Beyond cancer genetics, POLR2E participates in hepatoprotection through interaction with glutaminase 1, modulating RNA Pol II activity to regulate lipid metabolism in alcoholic liver disease 7. These findings establish POLR2E as both a fundamental transcriptional component and a clinically relevant biomarker for cancer predisposition and prognosis.