Alternative cleavage and polyadenylation: extent, regulation and function

Elkon, Ran; Ugalde, Alejandro P.; Agami, Reuven

doi:10.1038/nrg3482

Cited by 684 publications

(707 citation statements)

References 89 publications

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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%

“…Two main types of internal ALEs exist: 'skipped ALEs' are either skipped or included as terminal exons, whereas 'composite ALEs' can be included as either short internal exons or long terminal exons 7,8 . For bioinformatic analyses (Figs 2b-e and 5g,h), we compared DOXO-repressed internal skipped ALEs (n ¼ 62) with other internal skipped ALEs genome-wide (obtained from Genbank cDNAs).…”

Section: Methodsmentioning

confidence: 99%

“…Large numbers of alternatively spliced exons are coordinately regulated during various processes, including notably cell differentiation and cancer 1,2 , but studies mainy focused on cassette exons. 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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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 promoter and polyadenylation usage are two key mechanisms by which expression can be controlled transcriptionally or post-transcriptionally (Elkon et al 2013;de Klerk and 't Hoen 2015). Although the response of mBMDCs to LPS has been extensively characterized (Amit et al 2009;Garber et al 2012;Rabani et al 2014;Jovanovic et al 2015), the exact contribution of these two mechanisms to the transcriptional response to LPS is largely unknown.…”

Section: A Methods Specifically Designed For End-sequence Quantificationmentioning

confidence: 99%

End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data

et al. 2016

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RNA-seq protocols that focus on transcript termini are well suited for applications in which template quantity is limiting. Here we show that, when applied to end-sequencing data, analytical methods designed for global RNA-seq produce computational artifacts. To remedy this, we created the End Sequence Analysis Toolkit (ESAT). As a test, we first compared endsequencing and bulk RNA-seq using RNA from dendritic cells stimulated with lipopolysaccharide (LPS). As predicted by the telescripting model for transcriptional bursts, ESAT detected an LPS-stimulated shift to shorter 3 ′ -isoforms that was not evident by conventional computational methods. Then, droplet-based microfluidics was used to generate 1000 cDNA libraries, each from an individual pancreatic islet cell. ESAT identified nine distinct cell types, three distinct β-cell types, and a complex interplay between hormone secretion and vascularization. ESAT, then, offers a much-needed and generally applicable computational pipeline for either bulk or single-cell RNA end-sequencing.

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“…In particular, the less frequent intronic APA involves the recognition of a cryptic intronic poly(A) signal that involves premature polyadenylation within the coding region affecting the sequence of the protein (Elkon et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

LPS injection reprograms the expression and the 3′ UTR of a CAP gene by alternative polyadenylation and the formation of a GAIT element in Ciona intestinalis

Vizzini¹,

Bonura

Longo

et al. 2016

Molecular Immunology

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a b s t r a c tThe diversification of cellular functions is one of the major characteristics of multicellular organisms which allow cells to modulate their gene expression, leading to the formation of transcripts and proteins with different functions and concentrations in response to different stimuli. CAP genes represent a widespread family of proteins belonging to the cysteine-rich secretory protein, antigen 5 and pathogenesis-related 1 superfamily which, it has been proposed, play key roles in the infection process and the modulation of immune responses in host animals. The ascidian Ciona intestinalis represents a group of proto-chordates with an exclusively innate immune system that has been widely studied in the field of comparative and developmental immunology. Using this biological system, we describe the identification of a novel APA mechanism by which an intronic polyadenylation signal is activated by LPS injection, leading to the formation of a shorter CAP mRNA capable of expressing the first CAP exon plus 19 amino acid residues whose sequence is contained within the first intron of the annotated gene. Furthermore, such an APA event causes the expression of a translational controlling cis-acting GAIT element which is not present in the previously isolated CAP isoform and identified in the 3 -UTR of other immunerelated genes, suggesting an intriguing scenario in which both transcriptional and post-transcriptional control mechanisms are involved in the activation of the CAP gene during inflammatory response in C. intestinalis.

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Alternative cleavage and polyadenylation: extent, regulation and function

Cited by 684 publications

References 89 publications

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

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

End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data

LPS injection reprograms the expression and the 3′ UTR of a CAP gene by alternative polyadenylation and the formation of a GAIT element in Ciona intestinalis

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