DBR1 (debranching RNA lariats 1) is a nuclear enzyme that cleaves the 2'-5' phosphodiester linkage at the branch point of excised lariat intron RNAs, converting them into linear molecules for subsequent degradation and facilitating ribonucleotide turnover 1. DBR1 is the sole debranching activity in human cells and represents the rate-limiting step in intron lariat turnover 1. Beyond pre-mRNA processing, DBR1 plays a critical cell-intrinsic antiviral defense role: accumulation of RNA lariats in DBR1-deficient cells impairs stress granule assembly by promoting proteasome degradation of G3BP1/G3BP2, thereby impairing PKR activation and antiviral immunity 2. Inherited DBR1 deficiency causes acute viral encephalitis, particularly brainstem infection, with increased susceptibility to diverse viral infections including HSV-1 and SARS-CoV-2 3. Lariat accumulation in DBR1-deficient conditions chr3 attenuates dsRNA sensing pathways (MDA5, RIG-I, RNase L, PKR), reducing antiviral responses 4. In malignancy, decreased DBR1 expression in esophageal squamous cell carcinoma correlates with worse prognosis and serves as an independent predictor of poor outcomes 5. DBR1 was identified as an Alzheimer's disease risk gene in genome-wide association studies 6.