A Two-Layered Targeting Mechanism Underlies Nuclear RNA Sorting by the Human Exosome

Publication date: 18 February 2020Source: Cell Reports, Volume 30, Issue 7Author(s): Guifen Wu, Manfred Schmid, Leonor Rib, Patrik Polak, Nicola Meola, Albin Sandelin, Torben Heick JensenSummaryDegradation of transcripts in human nuclei is primarily facilitated by the RNA exosome. To obtain substrate specificity, the exosome is aided by adaptors; in the nucleoplasm, those adaptors are the nuclear exosome-targeting (NEXT) complex and the poly(A) (pA) exosome-targeting (PAXT) connection. How these adaptors guide exosome targeting remains enigmatic. Employing high-resolution 3′ end sequencing, we demonstrate that NEXT substrates arise from heterogenous and predominantly pA− 3′ ends often covering kilobase-wide genomic regions. In contrast, PAXT targets harbor well-defined pA+ 3′ ends defined by canonical pA site use. Irrespective of this clear division, NEXT and PAXT act redundantly in two ways: (1) regional redundancy, where the majority of exosome-targeted transcription units produce NEXT- and PAXT-sensitive RNA isoforms, and (2) isoform redundancy, where the PAXT connection ensures fail-safe decay of post-transcriptionally polyadenylated NEXT targets. In conjunction, this provides a two-layered targeting mechanism for efficient nuclear sorting of the human transcriptome.Graphical Abstract

Source: Cell Reports - February 19, 2020 Category: Cytology Source Type: research