Model for USB1 function in catalysis and in U6 snRNA quality control. (A) Model for USB1 3′-5′ exonuclease activity. The side-chain of H120 acts as a general base, abstracting a proton from the 2′ oxygen of the RNA substrate to facilitate nucleophilic attack on the phosphorus atom. The resulting in-line displacement of the leaving 5′ oxygen is favored by proton transfer from the side-chain of H208, which serves as a general acid. The RNA substrate is depicted in red. The figure was prepared using ChemBioDraw Ultra. (B) Model for USB1 function in U6 snRNA quality control. The length and 3′ end modification of U6 snRNA is dynamically regulated through the competing addition of UMP by terminal uridyl transferase (TUTase; 3′OH groups) and trimming by USB1 (3′ cyclic phosphate groups). In the absence of functional USB1 in poikiloderma with neutropenia, the polyA polymerase Trf4 3′ adenylates free 3′OH groups on U6 snRNA, targeting it for destruction by the exosome.