Abstract
A crucial feature of gene expression involves RNA processing to produce 3′ ends through a process termed 3′ end cleavage and polyadenylation (CPA). This ensures the nascent RNA molecule can exit the nucleus and be translated to ultimately give rise to a protein which can execute a function. Further, alternative polyadenylation (APA) can produce distinct transcript isoforms, profoundly expanding the complexity of the transcriptome. CPA is carried out by multi-component protein complexes interacting with multiple RNA motifs and is tightly coupled to transcription, other steps of RNA processing, and even epigenetic modifications. CPA and APA contribute to the maintenance of a multitude of diverse physiological processes. It is therefore not surprising that disruptions of CPA and APA can lead to devastating disorders. Here, we review potential CPA and APA mechanisms involving both loss and gain of function that can have tremendous impacts on health and disease. Ultimately we highlight the emerging diagnostic and therapeutic potential CPA and APA offer.
Highlights
In multicellular organisms almost every cell contains the same genome, yet complex spatial and temporal diversity is observed in gene transcripts
As 3.7% of the genetic variants detected in GWAS studies are localised within UTRs [284,285] and whole-genome sequencing has identified substantial UTR functional deregulation occurring in disease [286,287,288], it is imperative to unravel these mechanisms to fully understand the impact of cleavage and polyadenylation (CPA) and alternative polyadenylation (APA) on disease
Post-transcriptional gene regulation through mRNA 3 untranslated regions (3 UTR) sequences has emerged as a critical process controlling important cellular functions by directing transcript stability, nuclear export, sub-cellular localisation and translation efficiency
Summary
In multicellular organisms almost every cell contains the same genome, yet complex spatial and temporal diversity is observed in gene transcripts. CPA is initiated by this complex recognising specific cis-element sequences within the nascent pre-mRNA transcripts termed polyadenylation signals (PAS) [3]. The proper formation of the poly A tail in conjunction with the 3 untranslated regions (3 UTR) in the transcript directs stability, nuclear export, sub-cellular localisation and translation efficiency via cis-acting elements interacting with trans-acting factors, such as microRNAs (miRNA) or RNA-binding proteins (RBP) in given cellular contexts [38,39,40,41]. CPA can provide mechanisms for gene regulation through variations in the efficiency of CPA processing resulting from changing factor levels in trans [56,57] This is determined by cis PAS sequence elements of individual genes [58,59]
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