NRDE2 is a nuclear protein that functions as a critical regulator of RNA processing and quality control pathways. The protein localizes primarily to nuclear speckles where it negatively regulates the nuclear exosome by forming a 1:1 complex with the MTR4 helicase 1. NRDE2 inhibits MTR4 recruitment to the exosome and locks MTR4 in a closed conformation, preventing degradation of mRNAs and lncRNAs and thereby promoting their nuclear export 1. Additionally, NRDE2 serves as an essential RNA splicing factor, specifically suppressing intron retention in pre-mRNAs containing short, GC-rich introns with weak splice sites 2. The protein associates with U5 snRNP components and regulates splicing of critical transcripts like CEP131, which is essential for centrosome maturation and mitotic progression 2. Recent proteomic studies reveal NRDE2 interacts with transcriptional machinery including the PAF1 complex and RNA polymerase II, suggesting broader roles in gene expression 3. NRDE2 also contributes to DNA damage response and homologous recombination repair through its interaction with casein kinase 2, facilitating MDC1 phosphorylation 4. Loss-of-function mutations in NRDE2, such as the p.N377I variant, are associated with increased hepatocellular carcinoma susceptibility and sensitivity to PARP inhibitors 4.