Transcription termination by nuclear RNA polymerases

Richard, Patricia; Manley, James L.

doi:10.1101/gad.1792809

Cited by 289 publications

(335 citation statements)

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“…It was originally presumed that the 39 ends of mRNA are generated by direct transcriptional termination by RNA polymerase II (Pol II) rather than an RNA endonucleolytic cleavage reaction. Such a simple mechanism is well known to occur for prokaryotic polycistronic mRNA and also eukaryotic RNA polymerase III (Pol III) (Richard and Manley 2009). However, the fact that in vitro synthesized RNA, spanning a PAS, could be demonstrably cleaved and polyadenylated in vitro, which was first shown with mammalian nuclear extracts (Moore and Sharp 1985) and subsequently with yeast whole-cell extracts (Butler and Platt 1988), proved that mRNA 39-end formation and termination were separate, albeit connected, molecular events.…”

Section: Polyadenylation Signals and 39 Noncoding Rna (Ncrna) Sequencesmentioning

confidence: 99%

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Ending the message: poly(A) signals then and now

Proudfoot¹

2011

Genes Dev.

520

486

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Polyadenylation [poly(A)] signals (PAS) are a defining feature of eukaryotic protein-coding genes. The central sequence motif AAUAAA was identified in the mid1970s and subsequently shown to require flanking, auxiliary elements for both 39-end cleavage and polyadenylation of premessenger RNA (pre-mRNA) as well as to promote downstream transcriptional termination. More recent genomic analysis has established the generality of the PAS for eukaryotic mRNA. Evidence for the mechanism of mRNA 39-end formation is outlined, as is the way this RNA processing reaction communicates with RNA polymerase II to terminate transcription. The widespread phenomenon of alternative poly(A) site usage and how this interrelates with pre-mRNA splicing is then reviewed. This shows that gene expression can be drastically affected by how the message is ended. A central theme of this review is that while genomic analysis provides generality for the importance of PAS selection, detailed mechanistic understanding still requires the direct analysis of specific genes by genetic and biochemical approaches.

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Section: Polyadenylation Signals and 39 Noncoding Rna (Ncrna) Sequencesmentioning

confidence: 99%

“…This mechanism is called the torpedo model, and likely acts in consort with Pol II-recruited cleavage/poly(A) factors to promote efficient termination at a distinct 39 flanking region location, downstream from the gene, poly(A) site ( Fig. 3; Richard and Manley 2009;Kuehner et al 2011).…”

Section: Polyadenylation Signals and 39 Noncoding Rna (Ncrna) Sequencesmentioning

confidence: 99%

Ending the message: poly(A) signals then and now

Proudfoot¹

2011

Genes Dev.

520

486

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“…Statistical significance in a paired T-test for comparison with noncordycepin treated is indicated: (*) P # 0.05, (**) P # 0.01. This is a transcription termination defect that is observed if the efficiency of pre-mRNA cleavage is reduced (Luo et al 2006;West et al 2008;Richard and Manley 2009). We therefore examined the levels of uncleaved pre-mRNA and runthrough transcripts in total RNA isolated from ASM cells treated with cordycepin and TNF as described previously using RT-qPCR with the primers indicated in Figure 5E.…”

Section: Cordycepin Causes Transcription Termination and Cleavage Defmentioning

confidence: 99%

“…The efficiency of this step is dependent on the sequence of the polyadenylation signal and other elements in its close vicinity (Moore and Proudfoot 2009;Richard and Manley 2009;Wang et al 2010;Zhang et al 2010). Cleavage of the mRNA is also required for efficient termination of transcription by RNA polymerase II (Luo et al 2006;West et al 2008;Richard and Manley 2009). Termination is influenced by the rate of transcription elongation, by the efficiency of cleavage and polyadenylation, as well as by sequences found in the terminator region and in the promoter, giving rise to gene-specific effects on termination rates (Banerjee et al 2009;West and Proudfoot 2009;Milcarek et al 2011;Mukundan and Ansari 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Cleavage and polyadenylation factors are recruited to the RNA when the polyadenylation signal and surrounding sequences emerge from the RNA polymerase. The efficiency of this step is dependent on the sequence of the polyadenylation signal and other elements in its close vicinity (Moore and Proudfoot 2009;Richard and Manley 2009;Wang et al 2010;Zhang et al 2010). Cleavage of the mRNA is also required for efficient termination of transcription by RNA polymerase II (Luo et al 2006;West et al 2008;Richard and Manley 2009).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of polyadenylation reduces inflammatory gene induction

Kondrashov

Meijer

Barthet-Barateig

et al. 2012

RNA

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Cordycepin (39 deoxyadenosine) has long been used in the study of in vitro assembled polyadenylation complexes, because it terminates the poly(A) tail and arrests the cleavage complex. It is derived from caterpillar fungi, which are highly prized in Chinese traditional medicine. Here we show that cordycepin specifically inhibits the induction of inflammatory mRNAs by cytokines in human airway smooth muscle cells without affecting the expression of control mRNAs. Cordycepin treatment results in shorter poly(A) tails, and a reduction in the efficiency of mRNA cleavage and transcription termination is observed, indicating that the effects of cordycepin on 39 processing in cells are similar to those described in in vitro reactions. For the CCL2 and CXCL1 mRNAs, the effects of cordycepin are post-transcriptional, with the mRNA disappearing during or immediately after nuclear export. In contrast, although the recruitment of RNA polymerase II to the IL8 promoter is also unaffected, the levels of nascent transcript are reduced, indicating a defect in transcription elongation. We show that a reporter construct with 39 sequences from a histone gene is unaffected by cordycepin, while CXCL1 sequences confer cordycepin sensitivity to the reporter, demonstrating that polyadenylation is indeed required for the effect of cordycepin on gene expression. In addition, treatment with another polyadenyation inhibitor and knockdown of poly(A) polymerase a also specifically reduced the induction of inflammatory mRNAs. These data demonstrate that there are differences in the 39 processing of inflammatory and housekeeping genes and identify polyadenylation as a novel target for anti-inflammatory drugs.

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The Cell Nucleus: Biogenesis, Structure, and Function

Jackson

2011

Encyclopedia of Molecular Cell Biology and Molecular Medicine

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Transcription termination by nuclear RNA polymerases

Cited by 289 publications

References 288 publications

Ending the message: poly(A) signals then and now

Ending the message: poly(A) signals then and now

Inhibition of polyadenylation reduces inflammatory gene induction

The Cell Nucleus: Biogenesis, Structure, and Function

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