The nuclear RNA polymerase II surveillance system targets polymerase III transcripts

Wlotzka, Wiebke; Kudla, Grzegorz; Granneman, Sander; Tollervey, David

doi:10.1038/emboj.2011.97

Cited by 167 publications

(239 citation statements)

References 61 publications

(125 reference statements)

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“…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).…”

Section: Resultsmentioning

confidence: 99%

“…The precise binding sites for Nrd1 and Nab3 can be determined from the presence of T-to-C transitions caused by the 4-thiouracil cross-link (49,50). Using these T-to-C transitions to find the binding sites, we analyzed the top 40 Nab3 binding peaks among NCR genes and found common motifs corresponding to known Nrd1 and Nab3 binding sites (Table S1) (15)(16)(17)(18)(19). Using MEME software (51), we found that the Nrd1 consensus is present in fewer genes but is more statistically significant while the Nab3 consensus is present more often but contains less information (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

“…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).…”

mentioning

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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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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“…3). In CRAC and related techniques, an increased rate of microdeletions is seen in the sequence data at the site of protein crosslinking (19,(23)(24)(25)(26). This is attributable to errors introduced by reverse transcriptase when bypassing the crosslinked site and can be used to pinpoint the precise proteinbinding site.…”

Section: High-throughput Identification Of MCMV Rnas Associated Withmentioning

confidence: 99%

Murine cytomegalovirus encodes a miR-27 inhibitor disguised as a target

Libri

Helwak

Miesen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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115

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Individual microRNAs (miRNAs) are rapidly down-regulated during conditions of cellular activation and infection, but factors mediating miRNA turnover are poorly understood. Infection of mouse cells with murine cytomegalovirus (MCMV) induces the rapid down-regulation of an antiviral cellular miRNA, miR-27. Here, we identify a transcript produced by MCMV that binds to miR-27 and mediates its degradation. UV-crosslinking and high-throughput sequencing [CRAC (UV-crosslinking and analysis of cDNA)] identified MCMV RNA segments associated with the miRNA-binding protein Argonaute 2 (Ago2). A cluster of hits mapped to a predicted miR-27-binding site in the 3′UTR of the previously uncharacterized ORF, m169. The expression kinetics of the m169 transcript correlated with degradation of miR-27 during infection, and m169 expression inhibited miR-27 functional activity in a reporter assay. siRNA knockdown of m169 demonstrated its requirement for miR-27 degradation following infection and did not affect other host miRNAs. Substitution of the miR-27-binding site in m169 to create complementarity to a different cellular miRNA, miR-24, resulted in down-regulation of only miR-24 following infection. The m169 transcript is cytoplasmic, capped, polyadenylated, and interacts with miRNA-27 through seed pairing: characteristic features of the normal messenger RNA (mRNA) targets of miRNAs. This virus-host interaction reveals a mode of miRNA regulation in which a mRNA directs the degradation of a miRNA. We speculate that RNA-mediated miRNA degradation could be a more general viral strategy for manipulating host cells.V iruses devote a large portion of their genomes to strategies for manipulating host cells and evading antiviral defense mechanisms. Numerous host miRNA-binding sites have been predicted in different viral genomes, but the validity and functional relevance of most predictions remain unclear. The best studied miRNA-virus interactions demonstrate that RNA viruses can use cellular miRNAs to regulate their life cycles; for example, the interaction between hepatitis C virus and miR-122 enhances viral replication (1), whereas the interaction between HIV-1 and miR-29 mediates its localization to P bodies (2). Direct interactions between host miRNAs and viral genes can also suppress viral gene expression and replication (3-6) (reviewed in Ref. 7). However, the factors driving the evolution of these interactions remain somewhat controversial, because they may relate to viral mechanisms for persistence and latency rather than host defense (8, 9). At the same time, the expression levels of specific miRNAs can indirectly influence infections; miRNAs are key components of the innate immune response (10, 11) and exert antiviral properties by modulating host cofactors and pathways required by viruses (12-15). We previously showed that miR-27 limits the replication capacity of murine cytomegalovirus (MCMV) but is rapidly degraded during the lytic infection (16). Actinomycin D treatment upon infection prevents miR-27 down-regulation, suggest...

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Nuclear RNA surveillance: role of TRAMP in controlling exosome specificity

Schmidt

Butler

2013

WIREs RNA

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The advent of high throughput sequencing technologies has revealed that pervasive transcription generates RNAs from nearly all regions of eukaryotic genomes. Normally these transcripts undergo rapid degradation by a nuclear RNA surveillance system primarily featuring the RNA exosome. This multimeric protein complex plays a critical role in the efficient turnover and processing of a vast array of RNAs in the nucleus. Despite its initial discovery over a decade ago, important questions remain concerning the mechanisms that recruit and activate the nuclear exosome. Specificity and modulation of exosome activity requires additional protein cofactors, including the conserved TRAMP polyadenylation complex. Recent studies suggest that helicase and RNA binding subunits of TRAMP direct RNA substrates for polyadenylation, which enhances their degradation by Dis3/Rrp44 and Rrp6, the two exosome associated ribonucleases. These findings indicate that the exosome and TRAMP have evolved highly flexible functions that allow recognition of a wide range of RNA substrates. This flexibility provides the nuclear RNA surveillance system with the ability to regulate the levels of a broad range of coding and non-coding RNAs, which results in profound effects on gene expression, cellular development, gene silencing and heterochromatin formation. This review summarizes recent findings on the nuclear RNA surveillance complexes, and speculates upon possible mechanisms for TRAMP-mediated substrate recognition and exosome activation.

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The nuclear RNA polymerase II surveillance system targets polymerase III transcripts

Cited by 167 publications

References 61 publications

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

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

Murine cytomegalovirus encodes a miR-27 inhibitor disguised as a target

Nuclear RNA surveillance: role of TRAMP in controlling exosome specificity

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