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On the function and relevance of alternative 3′‐UTRs in gene expression regulation

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Abstract Messanger RNA (mRNA) isoforms with alternative 3′‐untranslated regions (3′‐UTRs) are produced by alternative polyadenylation (APA), which occurs during transcription in most eukaryotic genes. APA fine‐tunes gene expression in a cell‐type‐ and cellular state‐dependent manner. Selection of an APA site entails the binding of core cleavage and polyadenylation factors to a particular polyadenylation site localized in the pre‐mRNA and is controlled by multiple regulatory determinants, including transcription, pre‐mRNA cis‐regulatory sequences, and protein factors. Alternative 3′‐UTRs serve as platforms for specific RNA binding proteins and microRNAs, which regulate gene expression in a coordinated manner by controlling mRNA fate and function in the cell. Genome‐wide studies illustrated the full extent of APA prevalence and revealed that specific 3′‐UTR profiles are associated with particular cellular states and diseases. Generally, short 3′‐UTRs are associated with proliferative and cancer cells, and long 3′‐UTRs are mostly found in polarized and differentiated cells. Fundamental new insights on the physiological consequences of this widespread event and the molecular mechanisms involved have been revealed through single‐cell studies. Publicly available comprehensive databases that cover all APA mRNA isoforms identified in many cellular states and diseases reveal specific APA signatures. Therapies tackling APA mRNA isoforms or APA regulators may be regarded as innovative and attractive tools for diagnostics or treatment of several pathologies. We highlight the function of APA and alternative 3′‐UTRs in gene expression regulation, the control of these mechanisms, their physiological consequences, and their potential use as new biomarkers and therapeutic tools. This article is categorized under: RNA Processing > 3′ End Processing RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease
The three main types of alternative polyadenylation (APA): Coding region APA (CR‐APA), intronic APA (IPA), and 3′‐untranslated region APA (3′‐UTR‐APA). CR‐APA and IPA originate mRNA isoforms with different coding regions and 3′‐UTRs and are sometimes associated with alternative splicing. These two types of APA originate different proteins that differ in their C‐terminal region. The 3′‐UTR‐APA is the most common type of APA and originates mRNA isoforms that share the same coding region but have different 3′‐UTRs. The UTRs are depicted in gray; the coding region is represented by colored boxes and the polyadenylation signals (PAS) by black arrows
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Alternative 3′‐UTRs correlate with different physiological conditions. The biological conditions or diseases where a widespread shortening of the 3′‐UTRs was described are depicted in blue and the biological states with global 3′‐UTR lengthening are depicted in orange. Regulators of gene expression that bind to the alternative 3′‐UTRs are represented by RBP (RNA binding proteins) and miRNAs (microRNAs). PAS, polyadenylation signal and CDS, coding sequence
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Well‐established APA modulators. Protein factors that influence proximal PAS usage are listed in the orange box and regulators of distal PAS use are represented in the blue box. CDS: coding sequence; PAS: polyadenylation signal
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Schematic representation of the core 3′‐end processing machinery. Four main complexes compose the core 3′‐end processing complex: Cleavage and polyadenylation specificity factor (CPSF), represented in purple, cleavage factor I (CFIm), represented in dark blue, cleavage factor II (CFIIm), depicted in light blue, and cleavage stimulation factor (CstF), shown in orange. Symplekin is colored in yellow. While RNA polymerase II (RNAPII) is transcribing the DNA, some protein factors involved in polyadenylation travel along with RNAPII by interacting with its carboxyl‐terminal domain (CTD—green line). The PAS (AAUAAA) is located 15–30 nucleotides upstream of the cleavage and polyadenylation site. The endonucleolytic cleavage of the pre‐mRNA at the cleavage site by CPSF‐73 usually occurs between a cytosine/adenine (CA) dinucleotide after which a poly(A) polymerase (PAP) synthesizes a long poly(A) tail, stimulated by PABPN1 (in gray). USE, upstream sequence element
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RNA in Disease and Development > RNA in Disease
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Processing > 3′ End Processing

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