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

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

doi:10.1016/j.celrep.2020.01.068

Cited by 55 publications

(138 citation statements)

References 60 publications

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“…As many of these prematurely terminated transcripts are enriched in both PAXT and NEXT depletions, these transcripts are targeted by the exosome through different mechanisms. As reported previously ( 9 ), the recruitment of PAXT could occur through recognition of pA sites and conventional 3′end processing by the CPA machinery. NEXT could be recruited to these transcripts through its interaction with the CBC ( 62–64 ).…”

Section: Discussionsupporting

confidence: 66%

“…Exosome-directed decay of nuclear RNA is mediated by adaptor complexes ( 56 ). We therefore investigated which adaptor is implicated in the degradation of transcripts deriving from the four single exoTC classes, focusing on the PAXT connection and the NEXT complex, which primarily target longer polyadenylated and short non-adenylated transcripts, respectively ( 7 , 9 , 14 ). To enable such analysis, we prepared CAGE libraries from cells subjected to siRNA-depletion of ZFC3H1 (PAXT) or ZCCHC8 (NEXT), and plotted the distribution of CAGE exoTC sensitivity scores of siZFC3H1 versus Ctrl and siZCCHC8 versus Ctrl (Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

“…These can be lncRNAs, including subsets of enhancer RNAs (eRNAs) and promoter upstream transcripts (PROMPTs)/upstream antisense RNAs (uaRNAs) ( 10–13 ). The polyA exosome targeting (PAXT) connection targets similar RNA biotypes as the NEXT complex, but specifically those that are polyadenylated ( 9 ). Additionally, PAXT mediates the exosomal degradation of longer and processed nuclear RNAs ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

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The RNA exosome shapes the expression of key protein-coding genes

Karadoulama

Lloret-Llinares

et al. 2020

Nucleic Acids Research

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The ribonucleolytic exosome complex is central for nuclear RNA degradation, primarily targeting non-coding RNAs. Still, the nuclear exosome could have protein-coding (pc) gene-specific regulatory activities. By depleting an exosome core component, or components of exosome adaptor complexes, we identify ∼2900 transcription start sites (TSSs) from within pc genes that produce exosome-sensitive transcripts. At least 1000 of these overlap with annotated mRNA TSSs and a considerable portion of their transcripts share the annotated mRNA 3′ end. We identify two types of pc-genes, both employing a single, annotated TSS across cells, but the first type primarily produces full-length, exosome-sensitive transcripts, whereas the second primarily produces prematurely terminated transcripts. Genes within the former type often belong to immediate early response transcription factors, while genes within the latter are likely transcribed as a consequence of their proximity to upstream TSSs on the opposite strand. Conversely, when genes have multiple active TSSs, alternative TSSs that produce exosome-sensitive transcripts typically do not contribute substantially to overall gene expression, and most such transcripts are prematurely terminated. Our results display a complex landscape of sense transcription within pc-genes and imply a direct role for nuclear RNA turnover in the regulation of a subset of pc-genes.

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Section: Discussionsupporting

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The RNA exosome shapes the expression of key protein-coding genes

Karadoulama

Lloret-Llinares

et al. 2020

Nucleic Acids Research

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“…Considering that divergent transcription at TSSs is presumed to occur at most active protein coding genes (5,7,18-21), we expected a large number of PROMPTs in our Zcchc8 knockout cells. Recently, it was shown that the poly(A) exosome-targeting (PAXT) connection can act as a failsafe in the case of NEXT disruption (11). We wondered if NEXT complex redundancy through the PAXT connection would be evident through increased transcription or if the remaining NEXT complex components or RNA exosome were up-regulated as a compensatory mechanism for loss of ZCCHC8 function.…”

Section: Resultsmentioning

confidence: 99%

“…The nuclear exosome targeting complex (NEXT) is responsible for exosomal targeting of PROMPTs, enhancer RNAs (eRNAs), 3’ extended small nuclear RNAs (snRNAs), 3’ extended histone RNAs, and intronic RNAs (9-11). NEXT functions in the nucleoplasm and serves as an adapter complex that facilitates recognition and presentation of RNAs to the nuclear exosome (10-12).…”

Section: Introductionmentioning

confidence: 99%

ZCCHC8 is required for the degradation of pervasive transcripts originating from multiple genomic regulatory features

Collins

2021

Preprint

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The vast majority of mammalian genomes are transcribed as non-coding RNA in what is referred to as “pervasive transcription.” Recent studies have uncovered various families of non-coding RNA transcribed upstream of transcription start sites. In particular, highly unstable promoter upstream transcripts known as PROMPTs have been shown to be targeted for exosomal degradation by the nuclear exosome targeting complex (NEXT) consisting of the RNA helicase MTR4, the zinc-knuckle scaffold ZCCHC8, and the RNA binding protein RBM7. Here, we report that in addition to its known RNA substrates, ZCCHC8 is required for the targeted degradation of pervasive transcripts produced at CTCF binding sites, open chromatin regions, promoters, promoter flanking regions, and transcription factor binding sites. Additionally, we report that a significant number of RIKEN cDNAs and predicted genes display the hallmarks of PROMPTs and are also substrates for ZCCHC8 and/or NEXT complex regulation suggesting these are unlikely to be functional genes. Our results suggest that ZCCHC8 and/or the NEXT complex may play a larger role in the global regulation of pervasive transcription than previously reported.

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SKI complex: A multifaceted cytoplasmic RNA exosome cofactor in mRNA metabolism with links to disease, developmental processes, and antiviral responses

et al. 2023

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RNA stability and quality control are integral parts of gene expression regulation. A key factor shaping eukaryotic transcriptomes, mainly via 3′–5′ exoribonucleolytic trimming or degradation of diverse transcripts in nuclear and cytoplasmic compartments, is the RNA exosome. Precise exosome targeting to various RNA molecules requires strict collaboration with specialized auxiliary factors, which facilitate interactions with its substrates. The predominant class of cytoplasmic RNA targeted by the exosome are protein‐coding transcripts, which are carefully scrutinized for errors during translation. Normal, functional mRNAs are turned over following protein synthesis by the exosome or by Xrn1 5′–3′‐exonuclease, acting in concert with Dcp1/2 decapping complex. In turn, aberrant transcripts are eliminated by dedicated surveillance pathways, triggered whenever ribosome translocation is impaired. Cytoplasmic 3′–5′ mRNA decay and surveillance are dependent on the tight cooperation between the exosome and its evolutionary conserved co‐factor—the SKI (superkiller) complex (SKIc). Here, we summarize recent findings from structural, biochemical, and functional studies of SKIc roles in controlling cytoplasmic RNA metabolism, including links to various cellular processes. Mechanism of SKIc action is illuminated by presentation of its spatial structure and details of its interactions with exosome and ribosome. Furthermore, contribution of SKIc and exosome to various mRNA decay pathways, usually converging on recycling of ribosomal subunits, is delineated. A crucial physiological role of SKIc is emphasized by describing association between its dysfunction and devastating human disease—a trichohepatoenteric syndrome (THES). Eventually, we discuss SKIc functions in the regulation of antiviral defense systems, cell signaling and developmental transitions, emerging from interdisciplinary investigations.This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability RNA Interactions with Proteins and Other Molecules > RNA‐Protein Complexes

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

Cited by 55 publications

References 60 publications

The RNA exosome shapes the expression of key protein-coding genes

The RNA exosome shapes the expression of key protein-coding genes

ZCCHC8 is required for the degradation of pervasive transcripts originating from multiple genomic regulatory features

SKI complex: A multifaceted cytoplasmic RNA exosome cofactor in mRNA metabolism with links to disease, developmental processes, and antiviral responses

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