USB1 (U6 snRNA biogenesis phosphodiesterase 1) is a 3'-5' RNA exonuclease that trims the 3' ends of pre-U6 small nuclear RNA (snRNA), generating a mature U6 snRNA molecule terminated with a 2',3'-cyclic phosphate 12. This processing is essential for preventing U6 snRNA degradation and enabling proper spliceosome assembly 1. Beyond U6 snRNA maturation, USB1 functions as a microRNA deadenylase that preferentially removes adenylated tails from miRNA 3' ends with 20-fold greater efficiency than uridine removal 23. This deadenylase activity protects non-coding RNAs from degradation 4. Loss-of-function USB1 mutations cause poikiloderma with neutropenia (PN), a rare autosomal recessive disorder characterized by skin abnormalities, chr16 neutropenia, and increased infection/malignancy risk 5. PN-associated mutations impair hematopoietic development through dysregulated miRNA levels during blood development 3, and can cause skin fragility through downregulation of basement membrane zone genes 6. The molecular pathogenesis involves aberrant adenylation of U6 snRNA and dysregulation of miRNA processing when USB1 function is compromised 23. Therapeutic approaches targeting USB1's interaction partner PAPD5/7 may rescue hematopoiesis in PN patients 3.