DIS3L2 encodes a 3'-5' exoribonuclease that specifically recognizes and degrades polyuridylated RNAs in the cytoplasm 1. The enzyme contains RNA-binding domains (two CSD domains and one S1 domain) and an RNB catalytic domain responsible for exoribonuclease activity 1. DIS3L2 functions in cytoplasmic RNA surveillance by degrading uridylated substrates including pre-microRNAs, mature microRNAs, mRNAs, and other noncoding RNAs 12. The enzyme undergoes dramatic conformational changes triggered by double-stranded RNA, repositioning cold shock domains by 70 Å and exposing a trihelix linker that acts as a wedge to separate RNA strands 3. DIS3L2 plays crucial roles in preventing innate immune activation by degrading aberrant cellular RNAs that would otherwise trigger interferon responses 2. Loss of DIS3L2 function is associated with Perlman syndrome, an overgrowth disorder, and Wilms tumor predisposition 45. The enzyme controls cell proliferation through conserved pathways involving imaginal disc growth factors and PI3-Kinase/AKT signaling 4. Children with heterozygous germline DIS3L2 variants show increased rates of metastatic and high-risk blastemal Wilms tumors 5.