Key Points
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Recent advances in technologies for global mapping of alternative polyadenylation (APA) have allowed unprecedented investigation of alternative polyadenylation in biological processes.
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Broad APA modulation has been identified in development and cellular differentiation: in general in systems characterized thus far, development is accompanied by a progressive lengthening of 3′ untranslated regions (UTRs) and use of distal poly(A) sites.
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Cellular proliferation is associated with a use of shift towards proximal poly(A) sites.
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APA may be regulated by the level of 3′ end machinery expression, interplay with transcription, splicing and potentially chromatin.
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APA misregulation has been identified in human disease, and APA is potentially a therapeutic target.
Abstract
The 3′ end of most protein-coding genes and long non-coding RNAs is cleaved and polyadenylated. Recent discoveries have revealed that a large proportion of these genes contains more than one polyadenylation site. Therefore, alternative polyadenylation (APA) is a widespread phenomenon, generating mRNAs with alternative 3′ ends. APA contributes to the complexity of the transcriptome by generating isoforms that differ either in their coding sequence or in their 3′ untranslated regions (UTRs), thereby potentially regulating the function, stability, localization and translation efficiency of target RNAs. Here, we review our current understanding of the polyadenylation process and the latest progress in the identification of APA events, mechanisms that regulate poly(A) site selection, and biological processes and diseases resulting from APA.
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Acknowledgements
This work was supported by funds from the European Research Council (ERC), the Dutch cancer foundation (KWF), Horizon and the Netherlands Organisation for Scientific Research (VICI-NWO).
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Glossary
- Photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation
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(PAR-CLIP). A method for profiling RNA that is bound to a specific protein. Cells are grown in a medium containing 4-thiouridine or 6-thioguanosine, which, when incorporated into RNA, allows for efficient ultraviolet crosslinking to RNA-binding proteins. The immunoprecipitated protein–RNA complexes are then used to generate libraries for deep sequencing.
- Serial analysis of gene expression
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(SAGE). A method for quantitative and simultaneous analysis of a large number of transcripts; short sequence tags are isolated, concentrated and cloned; their sequencing reveals a gene expression pattern that is characteristic of the tissue or cell type from which the tags were isolated.
- Induced pluripotent stem cells
-
(iPSCs). Pluripotent stem cells that are artificially derived from non-pluripotent cells, typically by genetic manipulation.
- Striatal neurons
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Neurons that lie in the striatum, which is an area of the brain involved in fine movements, emotion and cognition.
- Hippocampal neurons
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Neurons that lie in the hippocampus, which is a neurogenic region of the forebrain that has an important functions in learning and memory.
- Immunoglobulin
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(Ig). An antigen receptor molecule produced by B cells that consists of two heavy chains and two light chains.
- Systematic evolution of ligands by exponential enrichment
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(SELEX). In the context of RNA, this is a method for identifying consensus protein-binding sequences on RNA substrates by in vitro selection of short RNAs that bind preferentially to RNA-binding proteins.
- Spliceosome
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A ribonucleoprotein complex that is involved in splicing nuclear precursor mRNA (pre-mRNA). It is composed of five small nuclear ribonucleoproteins (snRNPs) and more than 50 non-snRNPs, which recognize and assemble on exon–intron boundaries to catalyse intron processing of the pre-mRNA.
- Angiogenesis
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The formation of new blood vessels from pre-existing ones. It is often associated with cell division and the subsequent sprouting of the endothelial cells that contribute to the growing blood vessel.
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Elkon, R., Ugalde, A. & Agami, R. Alternative cleavage and polyadenylation: extent, regulation and function. Nat Rev Genet 14, 496–506 (2013). https://doi.org/10.1038/nrg3482
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DOI: https://doi.org/10.1038/nrg3482
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