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

TY - JOUR

T1 - A Two-Layered Targeting Mechanism Underlies Nuclear RNA Sorting by the Human Exosome

AU - Wu, Guifen

AU - Schmid, Manfred

AU - Rib, Leonor

AU - Polak, Patrik

AU - Meola, Nicola

AU - Sandelin, Albin

AU - Jensen, Torben Heick

N1 - Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2020/2/18

Y1 - 2020/2/18

N2 - 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.

AB - 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.

KW - 3′ end sequencing

KW - NEXT complex

KW - PAXT connection

KW - nuclear RNA turnover

KW - pA /pA RNA

UR - http://www.scopus.com/inward/record.url?scp=85079407806&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2020.01.068

DO - 10.1016/j.celrep.2020.01.068

M3 - Journal article

C2 - 32075771

SN - 2211-1247

VL - 30

SP - 2387

EP - 2401

JO - Cell Reports

JF - Cell Reports

IS - 7

ER -