DNTTIP2 coordinates RNA exosome activities to ensure fidelity of human ribosome assembly

Abstract

The RNA exosome-associated helicase Mtr4/MTR4 (yeast/human) is recruited by adaptor proteins bearing Arch-Interacting Motifs (AIMs) to selectively degrade RNA substrates. Although the exosome targets diverse RNAs, only a few adaptors have been identified. Here, we extend the inventory of human adaptors to include a pre-tRNA splicing-ligase complex component, a spliceosome-associated factor, and DNTTIP2, a constituent of the small ribosomal subunit (40S) precursor, the 90S pre-ribosome. Structure-guided studies reveal how the DNTTIP2AIM-docked processive exosome core and its associated distributive exonuclease EXOSC10, which contact distant sites on the 90S pre-ribosome, cooperate to degrade part of the 5′-external transcribed spacer (5’-ETS), a key RNA scaffold that coordinates early 40S assembly. By contrast, productive pre-ribosomal RNA trimming within the 90S pre-ribosome necessitates EXOSC10, which safeguards against uncontrolled processive degradation by the DNTTIP2AIM-docked exosome core. We propose that multivalent contacts provide a mechanistic framework by which the RNA exosome coordinates its distinct enzymatic activities, ensuring selective processing and surveillance during ribonucleoprotein particle maturation. Here the authors identify human adaptors of the RNA exosome bound helicase MTR4, linking RNA surveillance to tRNA splicing, pre-mRNA splicing, and ribosome assembly. They show how DNTTIP2 directs processive and distributive activities of the RNA exosome to ensure fidelity of human ribosome assembly.