POLR3F encodes RNA polymerase III subunit F, a peripheral component of RNA polymerase III (Pol III) that catalyzes transcription of DNA into RNA 1. As part of the POLR3C-POLR3F-POLR3G heterotrimer, POLR3F coordinates dynamics of Pol III stalk and clamp modules during transition from apo to elongation state 12. POLR3F enables Pol III synthesis of small non-coding RNAs including 5S rRNA, tRNAs, snRNAs, and miRNAs 3. Beyond transcription, POLR3F functions as a cytosolic DNA sensor detecting AT-rich double-stranded DNA, playing a critical role in innate immunity 4. POLR3F-mediated sensing of viral DNA, including varicella zoster virus (VZV) genomes, triggers type I interferon and NF-κB responses through the RIG-I pathway 564. Mutations in POLR3F cause Immunodeficiency 101 and predispose to severe VZV-induced CNS vasculitis and encephalitis 347. The R50W POLR3F mutation impairs antiviral responses to AT-rich DNA and increases viral replication 4. POLR3F heterozygosity increases VZV reactivation in neuronal cells, identifying POLR3F as a sentinel for VZV control during reactivation 7. Additionally, POLR3F associates with extrachromosomal circular DNA molecules to regulate gene expression 8.