POLR3C encodes RNA polymerase III subunit C, a peripheral component of the multisubunit RNA polymerase III (Pol III) complex 1. As part of the POLR3C/RPC3-POLR3F/RPC6-POLR3G/RPC7 heterotrimer, POLR3C coordinates dynamics of Pol III's stalk and clamp modules during transcription initiation and elongation. Pol III synthesizes small non-coding RNAs including 5S rRNA, snRNAs, tRNAs, and miRNAs from ~500 genomic loci. Beyond its transcriptional role, POLR3C functions as a cytosolic DNA sensor in innate immunity 2. It detects non-self dsDNA and endogenous mitochondrial DNA released during viral infection, triggering type I interferon responses through the RIG-I pathway 3. POLR3C preferentially binds single-stranded DNA in a sequence-independent manner. Clinically, heterozygous loss-of-function mutations in POLR3C cause monogenic or digenic immunodeficiency conferring susceptibility to severe varicella zoster virus encephalitis and pneumonitis in otherwise healthy children 3. Similarly, POLR3C variants impair type I interferon responses to SARS-CoV-2 infection and symptomatic acute hepatitis E 24. POLR3C mutations are also associated with hypomyelinating leukodystrophy and identified as tumor neoantigens in hepatocellular carcinoma 15.