Mechanisms and Consequences of Alternative Polyadenylation

Giammartino, Dafne Campigli Di; Nishida, Kensei; Manley, James L.

doi:10.1016/j.molcel.2011.08.017

Cited by 649 publications

(709 citation statements)

References 138 publications

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“…[52][53][54][55] Similarly, APA has a demonstrated regulatory role in human disease. 30,[56][57][58][59] Thus, coordinated APA and upstream AS could generate alternatively spliced mRNA isoforms with unique 3 0 UTRs that dictate mRNA half-lives and protein product functions (Fig. 1, right arm).…”

Section: Discussionmentioning

confidence: 99%

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

et al. 2016

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Alternative polyadenylation has been implicated as an important regulator of gene expression. In some cases, alternative polyadenylation is known to couple with alternative splicing to influence last intron removal. However, it is unknown whether alternative polyadenylation events influence alternative splicing decisions at upstream exons. Knockdown of the polyadenylation factors CFIm25 or CstF64 in HeLa cells was used as an approach in identifying alternative polyadenylation and alternative splicing events on a genome-wide scale. Although hundreds of alternative splicing events were found to be differentially spliced in the knockdown of CstF64, genes associated with alternative polyadenylation did not exhibit an increased incidence of alternative splicing. These results demonstrate that the coupling between alternative polyadenylation and alternative splicing is usually limited to defining the last exon. The striking influence of CstF64 knockdown on alternative splicing can be explained through its effects on UTR selection of known splicing regulators such as hnRNP A2/B1, thereby indirectly influencing splice site selection. We conclude that changes in the expression of the polyadenylation factor CstF64 influences alternative splicing through indirect effects.

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Section: Discussionmentioning

confidence: 99%

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

et al. 2016

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“…Thus, cell responses to DNA damage may involve the coordinated regulation of both nuclear and cytoplasmic sets of transcripts by HuR. Large-scale regulation of alternative polyadenylation and splicing are increasingly involved in cellular processes, including proliferation and genotoxic responses, respectively [1][2][3][4][5][6][7][8]16,[19][20][21] . In this context, our data provide several advances.…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, alternative polyA sites are widely regulated during several processes, most notably cell proliferation, where shorter forms are preferentially expressed [3][4][5][6][7] , but studies mainly focused on tandem polyA sites, which are located in the same exon. Thus, little is known about the regulation of alternative 3 0 terminal exons, also called alternative last exons (ALEs), which are found in 43,000 human genes and correspond to the alternative use of intronic polyA sites in a splicing-dependent manner [7][8][9] .…”

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confidence: 99%

“…In some genes, ALE isoforms have specialized functions (for example, IgM heavy chain and CT-CGRP genes) 8 . However, in general the 3 0 -most exon of a gene (referred to as the last ALE in this study) is viewed as producing the full-length isoform, while internal ALEs lead to less abundant and truncated isoforms, sometimes with dominant-negative properties [10][11][12] .…”

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confidence: 99%

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A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

et al. 2014

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Alternative 3 0 -terminal exons, which use intronic polyadenylation sites, are generally less conserved and expressed at lower levels than the last exon of genes. Here we discover a class of human genes, in which the last exon appeared recently during evolution, and the major gene product uses an alternative 3 0 -terminal exon corresponding to the ancestral last exon of the gene. This novel class of alternative 3 0 -terminal exons are downregulated on a large scale by doxorubicin, a cytostatic drug targeting topoisomerase II, and play a role in cell cycle regulation, including centromere-kinetochore assembly. The RNA-binding protein HuR/ ELAVL1 is a major regulator of this specific set of alternative 3 0 -terminal exons. HuR binding to the alternative 3 0 -terminal exon in the pre-messenger RNA promotes its splicing, and is reduced by topoisomerase inhibitors. These findings provide new insights into the evolution, function and molecular regulation of alternative 3 0 -terminal exons.

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“…In general, all mRNAs are thought to be cleaved soon after the cleavage site has been transcribed and, with the exception of histone mRNAs, become polyadenylated immediately afterward (Zhang et al 2010;Di Giammartino et al 2011;Proudfoot 2011). Cleavage and polyadenylation factors are recruited to the RNA when the polyadenylation signal and surrounding sequences emerge from the RNA polymerase.…”

Section: Introductionmentioning

confidence: 99%

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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Mechanisms and Consequences of Alternative Polyadenylation

Cited by 649 publications

References 138 publications

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

Inhibition of polyadenylation reduces inflammatory gene induction

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