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

Guifen Wu, Manfred Schmid, Leonor Rib, Patrik Polak, Nicola Meola, Albin Sandelin, Torben Heick Jensen

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

223 Downloads (Pure)


Degradation 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.

Original languageEnglish
JournalCell Reports
Pages (from-to)2387-2401
Number of pages15
Publication statusPublished - 2020


  • 3′ end sequencing
  • NEXT complex
  • PAXT connection
  • nuclear RNA turnover
  • pA /pA RNA


Dive into the research topics of 'A Two-Layered Targeting Mechanism Underlies Nuclear RNA Sorting by the Human Exosome'. Together they form a unique fingerprint.

Cite this