Transcriptome Surveillance by Selective Termination of Noncoding RNA Synthesis

Schulz, Daniel; Schwalb, Björn; Kiesel, Anja; Baejen, Carlo; Torkler, Phillipp; Gagneur, Julien; Soeding, Johannes; Cramer, Patrick

doi:10.1016/j.cell.2013.10.024

Cited by 202 publications

(404 citation statements)

References 76 publications

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“…Nuclear depletion of Nab3 results in readthrough transcription of snoRNA and CUTs as has been previously described for Nrd1 depletion (7,9,32,33,41). Figure 1A shows that snR47 and Nrd1 readthrough transcripts are slightly elevated in the FRB-tagged strain, and this level of readthrough is increased in the presence of rapamycin.…”

Section: Resultssupporting

confidence: 73%

“…In addition to noncoding RNAs, the NNS complex has been shown to bind to a number of mRNAs (7,15,19,35,43,44). However, despite the prevalence of Nrd1-Nab3 binding to the 5= end of mRNAs, there are relatively few genes where regulation by premature termination has been confirmed (7,15,35,41,43,45). Nrd1 expression is autoregulated through attenuation and is also sensitive to mutations in Nab3 (9,36).…”

Section: Resultsmentioning

confidence: 99%

“…We along with others have previously used the anchor-away strategy (40) to create conditional mutants of Nrd1 that lead to nuclear depletion in the presence of rapamycin (7,41). This approach has led to the identification of NNS termination sites and has identified a limited set of mRNAs that are controlled through NNS.…”

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Yeast RNA-Binding Protein Nab3 Regulates Genes Involved in Nitrogen Metabolism

Merran

Corden

2017

Molecular and Cellular Biology

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Termination of Saccharomyces cerevisiae RNA polymerase II (Pol II) transcripts occurs through two alternative pathways. Termination of mRNAs is coupled to cleavage and polyadenylation while noncoding transcripts are terminated through the Nrd1-Nab3-Sen1 (NNS) pathway in a process that is linked to RNA degradation by the nuclear exosome. Some mRNA transcripts are also attenuated through premature termination directed by the NNS complex. In this paper we present the results of nuclear depletion of the NNS component Nab3. As expected, many noncoding RNAs fail to terminate properly. In addition, we observe that nitrogen catabolite-repressed genes are upregulated by Nab3 depletion.KEYWORDS nitrogen metabolism, noncoding RNA, termination, transcription S accharomyces cerevisiae RNA polymerase II (Pol II) synthesizes both mRNAs and noncoding RNAs (ncRNAs), including snRNAs, snoRNAs, and a large number of RNAs with unknown functions (1, 2). The latter class includes cryptic unstable transcripts (CUTs) and stable uncharacterized transcripts (SUTs) (3, 4). Both coding and noncoding transcripts originate from promoters located in nucleosome-free regions in a process that requires both general transcription factors and gene-specific factors (5-7), but termination of these different classes of Pol II transcripts takes place through two different processes. Stable transcripts like mRNA and SUTs terminate through a process linked to cleavage and polyadenylation while snoRNAs and CUTs terminate through the Nrd1-Nab3-Sen1 (NNS) pathway (8)(9)(10)(11)(12)(13)(14).The NNS complex contains two RNA-binding proteins, Nrd1 and Nab3, which recognize specific sequences in nascent transcripts and direct termination in a process that requires the RNA helicase Sen1 (8,9,(15)(16)(17)(18)(19)(20). NNS interacts with Pol II in part through binding of Nrd1 to phosphorylated Ser5 on the C-terminal domain (CTD) (21-23), a pattern of CTD phosphorylation most prominent in the early stages of the transcription cycle, limiting NNS termination to promoter-proximal transcripts (24-29). The NNS complex also interacts with the TRAMP (Trf4/Trf5-Air1/Air2-Mtr4 polyadenylation) complex to couple termination to processing by the nuclear exosome (30)(31)(32)(33).While the two yeast Pol II termination pathways generally operate on distinct sets of transcripts, there are some genes that can use either termination pathway (11). In some cases NNS acts downstream of genes as a fail-safe termination mechanism to ensure that transcripts that fail to terminate through the cleavage/polyadenylation mechanism do not read through into downstream genes (34,35). In other cases NNS functions upstream to terminate transcripts before the poly(A) site is reached. For example, Nrd1 autoregulates its own transcription by binding, along with Nab3, to sites in the 5= end of its nascent pre-mRNA (9, 36). The result of this binding leads to premature termination of the majority of Nrd1 transcripts close to the 5= end. Nrd1 transcripts that escape the NNS pathway go on to t...

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Section: Resultssupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

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Yeast RNA-Binding Protein Nab3 Regulates Genes Involved in Nitrogen Metabolism

Merran

Corden

2017

Molecular and Cellular Biology

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“…Comparative analysis of RNA expressed in wild-type yeast strains and in mutant strains where the exosome complex exoribonuclease Rrp6 has been deleted, identified two new classes of ncRNAs, the stable unannotated transcripts (SUTs), and the cryptic unstable transcripts (CUTs) (Xu et al 2009). Subsequent studies in strains where the cytoplasmic exonuclease Xrn1 has been disrupted, the histone methyltransferase Set2 has been deleted or depletion of the RNA-binding factor Nrd1 identified further classes of ncRNAs, termed Xrn1-sensitive unstable transcripts (XUTs) (van Dijk et al 2011;Wery et al 2016), Set2-repressed antisense transcripts (SRATs) (Venkatesh et al 2016) and Nrd1-unterminated transcripts (NUTs) (Schulz et al 2013), respectively. Almost half of the identified XUTs, SRATs, and NUTs overlap with a SUT or CUT.…”

Section: Introductionmentioning

confidence: 99%

A resource for functional profiling of noncoding RNA in the yeast Saccharomyces cerevisiae

Parker¹,

Fraczek²,

et al. 2017

RNA

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Eukaryotic genomes are extensively transcribed, generating many different RNAs with no known function. We have constructed 1502 molecular barcoded ncRNA gene deletion strains encompassing 443 ncRNAs in the yeast Saccharomyces cerevisiae as tools for ncRNA functional analysis. This resource includes deletions of small nuclear RNAs (snRNAs), transfer RNAs (tRNAs), small nucleolar RNAs (snoRNAs), and other annotated ncRNAs as well as the more recently identified stable unannotated transcripts (SUTs) and cryptic unstable transcripts (CUTs) whose functions are largely unknown. Specifically, deletions have been constructed for ncRNAs found in the intergenic regions, not overlapping genes or their promoters (i.e., at least 200 bp minimum distance from the closest gene start codon). The deletion strains carry molecular barcodes designed to be complementary with the protein gene deletion collection enabling parallel analysis experiments. These strains will be useful for the numerous genomic and molecular techniques that utilize deletion strains, including genome-wide phenotypic screens under different growth conditions, pooled chemogenomic screens with drugs or chemicals, synthetic genetic array analysis to uncover novel genetic interactions, and synthetic dosage lethality screens to analyze gene dosage. Overall, we created a valuable resource for the RNA community and for future ncRNA research.

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“…CUTs are terminated by a distinct, poly(A)-independent pathway that depends on Nrd1 and Nab3, two RNA-binding proteins that are not highly conserved in multicellular organisms, and the RNA helicase Sen1 (Kim et al 2006;Carroll et al 2007;Vasiljeva et al 2008;Mischo and Proudfoot 2013). The Nrd1-Nab3-Sen1 complex associates with Pol II during early elongation (Vasiljeva et al 2008), binds to short sequence motifs that are enriched in CUTs (Schulz et al 2013) and induces termination and degradation of these RNAs by the nuclear exosome. The yeast Nrd1 pathway is also used to terminate transcription of short, structured RNAs, e.g., small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs), whose 3 ′ ends are trimmed by the nuclear exosome.…”

Section: Introductionmentioning

confidence: 99%

Suppressor of sable [Su(s)] and Wdr82 down-regulate RNA from heat-shock-inducible repetitive elements by a mechanism that involves transcription termination

Brewer-Jensen

Wilson

Abernethy

et al. 2015

RNA

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Although RNA polymerase II (Pol II) productively transcribes very long genes in vivo, transcription through extragenic sequences often terminates in the promoter-proximal region and the nascent RNA is degraded. Mechanisms that induce early termination and RNA degradation are not well understood in multicellular organisms. Here, we present evidence that the suppressor of sable [su(s)] regulatory pathway of Drosophila melanogaster plays a role in this process. We previously showed that Su(s) promotes exosome-mediated degradation of transcripts from endogenous repeated elements at an Hsp70 locus (Hsp70-αβ elements). In this report, we identify Wdr82 as a component of this process and show that it works with Su(s) to inhibit Pol II elongation through Hsp70-αβ elements. Furthermore, we show that the unstable transcripts produced during this process are polyadenylated at heterogeneous sites that lack canonical polyadenylation signals. We define two distinct regions that mediate this regulation. These results indicate that the Su(s) pathway promotes RNA degradation and transcription termination through a novel mechanism.

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Transcriptome Surveillance by Selective Termination of Noncoding RNA Synthesis

Cited by 202 publications

References 76 publications

Yeast RNA-Binding Protein Nab3 Regulates Genes Involved in Nitrogen Metabolism

Yeast RNA-Binding Protein Nab3 Regulates Genes Involved in Nitrogen Metabolism

A resource for functional profiling of noncoding RNA in the yeast Saccharomyces cerevisiae

Suppressor of sable [Su(s)] and Wdr82 down-regulate RNA from heat-shock-inducible repetitive elements by a mechanism that involves transcription termination

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